77 results on '"Zhengui Xia"'
Search Results
2. Dynamics of a hippocampal neuronal ensemble encoding trace fear memory revealed by in vivo Ca2+ imaging.
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Liang Zhang, Xuanmao Chen, Carlos Sindreu, Song Lu, Daniel R Storm, Larry S Zweifel, and Zhengui Xia
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Medicine ,Science - Abstract
Although the biochemical signaling events in area CA1 of the hippocampus underlying memory acquisition, consolidation, retrieval, and extinction have been extensively studied, little is known about the activity dynamics of hippocampal neurons in CA1 during Pavlovian fear conditioning. Here, we use fiber-optic confocal microscopy coupled with the calcium indicator GCaMP6m to monitor neuron activity in freely moving mice during trace fear conditioning. We show that the activity of a group of CA1 neurons increases not only after the stimulus presentations, but also during the stimulus-free trace period when the conditioned mice exhibit a high level of freezing behavior. Therefore, we designate these cells "trace cells". Interestingly, the activity of the trace cells increases in response to the conditioned stimuli during memory retrieval but diminishes during memory extinction. Importantly, the dynamics of neuron activity exhibit a high degree of correlation with the freezing behavior of the mice, suggesting that a neuronal ensemble responsible for encoding the trace fear memory is repeatedly reactivated during memory retrieval and later extinguished during memory extinction.
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- 2019
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3. Correction to: Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice
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Anna K. Engstrom, Jessica M. Snyder, Nobuyo Maeda, and Zhengui Xia
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Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract ᅟ
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- 2017
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4. The type 3 adenylyl cyclase is required for the survival and maturation of newly generated granule cells in the olfactory bulb.
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Jie Luo, Xuanmao Chen, Yung-Wei Pan, Song Lu, Zhengui Xia, and Daniel R Storm
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Medicine ,Science - Abstract
The type 3 adenylyl cyclase (AC3) is localized to olfactory cilia in the main olfactory epithelium (MOE) and primary cilia in the adult mouse brain. Although AC3 has been strongly implicated in odor perception and olfactory sensory neuron (OSN) targeting, its role in granule cells (GCs), the most abundant interneurons in the main olfactory bulb (MOB), remains largely unknown. Here, we report that the deletion of AC3 leads to a significant reduction in the size of the MOB as well as the level of adult neurogenesis. The cell proliferation and cell cycle in the subventricular zone (SVZ), however, are not suppressed in AC3-/- mice. Furthermore, AC3 deletion elevates the apoptosis of GCs and disrupts the maturation of newly formed GCs. Collectively, our results identify a fundamental role for AC3 in the development of adult-born GCs in the MOB.
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- 2015
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5. Electroolfactogram (EOG) Recording in the Mouse Main Olfactory Epithelium
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Xuanmao Chen, Zhengui Xia, and Daniel Storm
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Biology (General) ,QH301-705.5 - Abstract
Olfactory sensory neurons in the main olfactory epithelium (MOE) are responsible for detecting odorants and EOG recording is a reliable approach to analyze the peripheral olfactory function. However, recently we revealed that rodent MOE can also detect the air pressure caused by airflow. The sensation of airflow pressure and odorants may function in synergy to facilitate odorant perception during sniffing. We have reported that the pressure-sensitive response in the MOE can also be assayed by EOG recording. Here we describe procedures for pressure-sensitive as well as odorant-stimulated EOG measurement in the mouse MOE. The major difference between the pressure-sensitive EOG response and the odorant-stimulated response was whether to use pure air puff or use an odorized air puff.
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- 2013
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6. Correction: Inducible and Targeted Deletion of the ERK5 MAP Kinase in Adult Neurogenic Regions Impairs Adult Neurogenesis in the Olfactory Bulb and Several Forms of Olfactory Behavior.
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Yung-Wei Pan, Chay T. Kuo, Daniel R. Storm, and Zhengui Xia
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Medicine ,Science - Published
- 2013
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7. Conditional deletion of ERK5 MAP kinase in the nervous system impairs pheromone information processing and pheromone-evoked behaviors.
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Junhui Zou, Daniel R Storm, and Zhengui Xia
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Medicine ,Science - Abstract
ERK5 MAP kinase is highly expressed in the developing nervous system but absent in most regions of the adult brain. It has been implicated in regulating the development of the main olfactory bulb and in odor discrimination. However, whether it plays an essential role in pheromone-based behavior has not been established. Here we report that conditional deletion of the Mapk7 gene which encodes ERK5 in mice in neural stem cells impairs several pheromone-mediated behaviors including aggression and mating in male mice. These deficits were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression. Using mouse urine as a natural pheromone-containing solution, we provide evidence that the behavior impairment was associated with defects in the detection of closely related pheromones as well as with changes in their innate preference for pheromones related to sexual and reproductive activities. We conclude that expression of ERK5 during development is critical for pheromone response and associated animal behavior in adult mice.
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- 2013
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8. Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb.
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Tan Li, Yung-Wei Pan, Wenbin Wang, Glen Abel, Junhui Zou, Lihong Xu, Daniel R Storm, and Zhengui Xia
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Medicine ,Science - Abstract
Recent studies have led to the exciting idea that adult-born neurons in the olfactory bulb (OB) may be critical for complex forms of olfactory behavior in mice. However, signaling mechanisms regulating adult OB neurogenesis are not well defined. We recently reported that extracellular signal-regulated kinase (ERK) 5, a MAP kinase, is specifically expressed in neurogenic regions within the adult brain. This pattern of expression suggests a role for ERK5 in the regulation of adult OB neurogenesis. Indeed, we previously reported that conditional deletion of erk5 in adult neurogenic regions impairs several forms of olfactory behavior in mice. Thus, it is important to understand how ERK5 regulates adult neurogenesis in the OB. Here we present evidence that shRNA suppression of ERK5 in adult neural stem/progenitor cells isolated from the subventricular zone (SVZ) reduces neurogenesis in culture. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, stimulates neurogenesis. Furthermore, inducible and conditional deletion of erk5 specifically in the neurogenic regions of the adult mouse brain interferes with cell cycle exit of neuroblasts, impairs chain migration along the rostral migratory stream and radial migration into the OB. It also inhibits neuronal differentiation and survival. These data suggest that ERK5 regulates multiple aspects of adult OB neurogenesis and provide new insights concerning signaling mechanisms governing adult neurogenesis in the SVZ-OB axis.
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- 2013
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9. Inducible and targeted deletion of the ERK5 MAP kinase in adult neurogenic regions impairs adult neurogenesis in the olfactory bulb and several forms of olfactory behavior.
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Yung-Wei Pan, Chay T Kuo, Daniel R Storm, and Zhengui Xia
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Medicine ,Science - Abstract
Although adult-born neurons in the subventricular zone (SVZ) and olfactory bulb (OB) have been extensively characterized at the cellular level, their functional impact on olfactory behavior is still highly controversial with many conflicting results reported in the literature. Furthermore, signaling mechanisms regulating adult SVZ/OB neurogenesis are not well defined. Here we report that inducible and targeted deletion of erk5, a MAP kinase selectively expressed in the adult neurogenic regions of the adult brain, impairs adult neurogenesis in the SVZ and OB of transgenic mice. Although erk5 deletion had no effect on olfactory discrimination among discrete odorants in the habituation/dishabituation assay, it reduced short-term olfactory memory as well as detection sensitivity to odorants and pheromones including those evoking aggression and fear. Furthermore, these mice show impaired acquisition of odor-cued associative olfactory learning, a novel phenotype that had not been previously linked to adult neurogenesis. These data suggest that ERK5 MAP kinase is a critical kinase signaling pathway regulating adult neurogenesis in the SVZ/OB, and provide strong evidence supporting a functional role for adult neurogenesis in several distinct forms of olfactory behavior.
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- 2012
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10. The maintenance of established remote contextual fear memory requires ERK5 MAP kinase and ongoing adult neurogenesis in the hippocampus.
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Yung-Wei Pan, Daniel R Storm, and Zhengui Xia
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Medicine ,Science - Abstract
Adult neurogenesis in the dentate gyrus of the hippocampal formation has been implicated in several forms of hippocampus-dependent memory. However, its role in the persistence of remote memory is unknown. Furthermore, whether the hippocampus plays a role in maintaining remote contextual memories is controversial. Here we used an inducible gene-specific approach for conditional deletion of erk5 in the adult neurogenic regions of the mouse brain to specifically impair adult neurogenesis. The erk5 gene was conditionally deleted under three different experimental conditions: prior to training for contextual fear, 6 days after training, or 5 weeks after training, We present evidence that remote memory was impaired under all three conditions. These data demonstrate that ongoing adult neurogenesis is required both for the initial establishment and the continued maintenance of remote contextual fear memory, even after the remote memory has transferred into extra-hippocampal regions of the brain 5 weeks after training.
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- 2012
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11. Adult type 3 adenylyl cyclase-deficient mice are obese.
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Zhenshan Wang, Vicky Li, Guy C K Chan, Trongha Phan, Aaron S Nudelman, Zhengui Xia, and Daniel R Storm
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Medicine ,Science - Abstract
BACKGROUND:A recent study of obesity in Swedish men found that polymorphisms in the type 3 adenylyl cyclase (AC3) are associated with obesity, suggesting the interesting possibility that AC3 may play a role in weight control. Therefore, we examined the weight of AC3 mice over an extended period of time. METHODOLOGY/PRINCIPAL FINDINGS:We discovered that AC3(-/-) mice become obese as they age. Adult male AC3(-/-) mice are about 40% heavier than wild type male mice while female AC3(-/-) are 70% heavier. The additional weight of AC3(-/-) mice is due to increased fat mass and larger adipocytes. Before the onset of obesity, young AC3(-/-) mice exhibit reduced physical activity, increased food consumption, and leptin insensitivity. Surprisingly, the obesity of AC3(-/-) mice is not due to a loss of AC3 from white adipose and a decrease in lipolysis. CONCLUSIONS/SIGNIFICANCE:We conclude that mice lacking AC3 exhibit obesity that is apparently caused by low locomotor activity, hyperphagia, and leptin insensitivity. The presence of AC3 in primary cilia of neurons of the hypothalamus suggests that cAMP signals generated by AC3 in the hypothalamus may play a critical role in regulation of body weight.
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- 2009
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12. ERK5 MAP kinase regulates neurogenin1 during cortical neurogenesis.
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Paige Cundiff, Lidong Liu, Yupeng Wang, Junhui Zou, Yung-Wei Pan, Glen Abel, Xin Duan, Guo-Li Ming, Chris Englund, Robert Hevner, and Zhengui Xia
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Medicine ,Science - Abstract
The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors.
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- 2009
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13. Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition
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Wenbin Wang, Nathanael S. Gray, Adam J. Pearson, William Vermi, Zhengui Xia, Katherine G. Finegan, Jinhua Wang, Ilaria Russo, Silvia Lonardi, Cathy Tournier, Qiuping Xu, Brian A. Telfer, and Emanuele Giurisato
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0301 basic medicine ,MAPK/ERK pathway ,Medical Sciences ,medicine.medical_treatment ,Antigens, CD/metabolism ,Inbred C57BL ,ERK5, MAPK, STAT3, macrophages, tumors ,Transgenic ,STAT3 ,Mice ,Mitogen-Activated Protein Kinase 7/genetics ,Cancer immunotherapy ,Neoplasms ,Receptors ,Macrophage ,Phosphorylation ,Multidisciplinary ,biology ,Manchester Cancer Research Centre ,Cell Polarity ,Biological Sciences ,CD ,ERK5 ,Manchester Institute for Collaborative Research on Ageing ,PNAS Plus ,Macrophages ,MAPK ,Tumors ,Animals ,Antigens, CD ,Antigens, Differentiation, Myelomonocytic ,Humans ,Mice, Inbred C57BL ,Mice, Transgenic ,Mitogen-Activated Protein Kinase 7 ,Receptors, Cell Surface ,STAT3 Transcription Factor ,Tyrosine ,Xenograft Model Antitumor Assays ,Differentiation ,Cell Surface ,Antigens, Differentiation, Myelomonocytic/metabolism ,Tyrosine/metabolism ,Neoplasms/metabolism ,ResearchInstitutes_Networks_Beacons/MICRA ,STAT3 Transcription Factor/genetics ,Macrophage polarization ,Proinflammatory cytokine ,QH301 ,03 medical and health sciences ,Macrophages/metabolism ,medicine ,Antigens ,Protein kinase A ,Receptors, Cell Surface/metabolism ,QH ,ResearchInstitutes_Networks_Beacons/mcrc ,Myelomonocytic ,030104 developmental biology ,biology.protein ,Cancer research ,STAT protein - Abstract
Significance Macrophages can be functionally reprogrammed by the tumor microenvironment to further tumor growth and malignancy. In this study, we have discovered that this pathological process is dependent on the ERK5 MAPK. Accordingly, we demonstrated that inactivation of ERK5 in macrophages blocked the phosphorylation of STAT3, a transcription factor crucial for determining macrophage polarity, and impaired the growth of melanoma and carcinoma grafts. These results raise the possibility that targeting protumor macrophages via anti-ERK5 therapy constitutes a very attractive strategy for cancer treatment. This is important given that the detection of large numbers of macrophages in human tumors often correlates with poor prognosis, but also with a poor response of the tumor to anticancer agents., Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.
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- 2018
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14. Correction to: Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice
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Zhengui Xia, Jessica M. Snyder, Anna K. Engstrom, and Nobuyo Maeda
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0301 basic medicine ,Male ,medicine.medical_specialty ,Neurology ,Apolipoprotein E4 ,Mice, Transgenic ,lcsh:Geriatrics ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Alzheimer Disease ,medicine ,Organometallic Compounds ,Animals ,Humans ,Apolipoprotein e4 ,Gene Knock-In Techniques ,Gene–environment interaction ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Behavior, Animal ,Correction ,Brain ,Cognition ,Immunohistochemistry ,lcsh:RC952-954.6 ,Disease Models, Animal ,030104 developmental biology ,Female ,Gene-Environment Interaction ,Neurology (clinical) ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Alzheimer's disease (AD) is characterized by progressive cognitive decline and memory loss. Environmental factors and gene-environment interactions (GXE) may increase AD risk, accelerate cognitive decline, and impair learning and memory. However, there is currently little direct evidence supporting this hypothesis.In this study, we assessed for a GXE between lead and ApoE4 on cognitive behavior using transgenic knock-in (KI) mice that express the human Apolipoprotein E4 allele (ApoE4-KI) or Apolipoprotein E3 allele (ApoE3-KI). We exposed 8-week-old male and female ApoE3-KI and ApoE4-KI mice to 0.2% lead acetate via drinking water for 12 weeks and assessed for cognitive behavior deficits during and after the lead exposure. In addition, we exposed a second (cellular) cohort of animals to lead and assessed for changes in adult hippocampal neurogenesis as a potential underlying mechanism for lead-induced learning and memory deficits.In the behavior cohort, we found that lead reduced contextual fear memory in all animals; however, this decrease was greatest and statistically significant only in lead-treated ApoE4-KI females. Similarly, only lead-treated ApoE4-KI females exhibited a significant decrease in spontaneous alternation in the T-maze. Furthermore, all lead-treated animals developed persistent spatial working memory deficits in the novel object location test, and this deficit manifested earlier in ApoE4-KI mice, with female ApoE4-KI mice exhibiting the earliest deficit onset. In the cellular cohort, we observed that the maturation, differentiation, and dendritic development of adult-born neurons in the hippocampus was selectively impaired in lead-treated female ApoE4-KI mice.These data suggest that GXE between ApoE4 and lead exposure may contribute to cognitive impairment and that impaired adult hippocampal neurogenesis may contribute to these deficits in cognitive behavior. Together, these data suggest a role for GXE and sex differences in AD risk.
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- 2017
15. Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons
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Zhengui Xia, Hyung-Wook Kim, Richard D. Palmiter, François Tronche, Won Seok Choi, Daniel R. Storm, University of Washington [Seattle], Chonnam National University [Gwangju], Sejong University, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), and HAL UPMC, Gestionnaire
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Male ,0301 basic medicine ,Serotonin ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Neurite ,Dopamine ,Substantia nigra ,Striatum ,Anxiety ,Motor Activity ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Conditional gene knockout ,medicine ,Animals ,Cognitive Dysfunction ,Maze Learning ,Mice, Knockout ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Electron Transport Complex I ,Multidisciplinary ,Behavior, Animal ,Cell Death ,Pars compacta ,Dopaminergic Neurons ,Dopaminergic ,Parkinson Disease ,medicine.disease ,Corpus Striatum ,Substantia Nigra ,Disease Models, Animal ,030104 developmental biology ,nervous system ,Anesthesia ,Neuroscience ,Gene Deletion ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug - Abstract
Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss.
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- 2017
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16. p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65
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Beibei Cai, Azad Bonni, Zhengui Xia, Esther B. E. Becker, and Sandra H. Chang
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Programmed cell death ,Arsenites ,Cell Survival ,p38 mitogen-activated protein kinases ,Apoptosis ,Biology ,Transfection ,Biochemistry ,PC12 Cells ,p38 Mitogen-Activated Protein Kinases ,Proto-Oncogene Proteins ,Serine ,Animals ,Enzyme Inhibitors ,Phosphorylation ,Protein kinase A ,Molecular Biology ,Bcl-2-Like Protein 11 ,Kinase ,Wild type ,Membrane Proteins ,Cell Biology ,Sodium Compounds ,Cell biology ,Protein Structure, Tertiary ,Rats ,Oxidative Stress ,Mitogen-activated protein kinase ,biology.protein ,Apoptosis Regulatory Proteins - Abstract
The stress-activated c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) regulate apoptosis induced by several forms of cellular insults. Potential targets for these kinases include members of the Bcl-2 family proteins, which mediate apoptosis generated through the mitochondria-initiated, intrinsic cell death pathway. Indeed, the activities of several Bcl-2 family proteins, both pro- and anti-apoptotic, are controlled by JNK phosphorylation. For example, the pro-apoptotic activity of Bim(EL), a member of the Bcl-2 family, is stimulated by JNK phosphorylation at Ser-65. In contrast, there is no reported evidence that p38-induced apoptosis is due to direct phosphorylation of Bcl-2 family proteins. Here we report evidence that sodium arsenite-induced apoptosis in PC12 cells may be due to direct phosphorylation of Bim(EL) at Ser-65 by p38. This conclusion is supported by data showing that ectopic expression of a wild type, but not a non-phosphorylatable S65A mutant of Bim(EL), potentiates sodium arsenite-induced apoptosis and by experiments showing direct phosphorylation of Bim(EL) at Ser-65 by p38 in vitro. Furthermore, sodium arsenite induced Bim(EL) phosphorylation at Ser-65, which was blocked by p38 inhibition. This study provides the first example whereby p38 induces apoptosis by phosphorylating a member of the Bcl-2 family and illustrates that phosphorylation of Bim(EL) on Ser-65 may be a common regulatory point for cell death induced by both JNK and p38 pathways.
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- 2016
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17. Regulation of the G2–M cell cycle progression by the ERK5–NFκB signaling pathway
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Cun-Yu Wang, Zhengui Xia, Hyun Jung Choi, Kelly Cude, Yupeng Wang, Honglai Zhang, and Shih-Ling Hsuan
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G2 Phase ,Cyclin A ,Mitosis ,Polo-like kinase ,Ribosomal Protein S6 Kinases, 90-kDa ,Article ,Cell Line ,Ribosomal s6 kinase ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Cyclin B1 ,Research Articles ,Mitogen-Activated Protein Kinase 7 ,030304 developmental biology ,Cyclin ,0303 health sciences ,Cyclin-dependent kinase 1 ,biology ,NF-kappa B ,Cell Biology ,Cell cycle ,3. Good health ,Cell biology ,030220 oncology & carcinogenesis ,biology.protein ,I-kappa B Proteins ,Signal transduction ,HeLa Cells ,Signal Transduction - Abstract
Elucidation of mechanisms regulating cell cycle progression is of fundamental importance for cell and cancer biology. Although several genes and signaling pathways are implicated in G1-S regulation, less is known regarding the mechanisms controlling cell cycle progression through G2 and M phases. We report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinases, is activated at G2-M and required for timely mitotic entry. Stimulation of ERK5 activated nuclear factor kappaB (NFkappaB) through ribosomal S6 kinase 2 (RSK2)-mediated phosphorylation and degradation of IkappaB. Furthermore, selective inhibition of NFkappaB at G2-M phases substantially delayed mitotic entry and inhibited transcription of G2-M-specific genes, including cyclin B1, cyclin B2, Plk-1, and cdc25B. Moreover, inhibition of NFkappaB at G2-M diminished mitosis induced by constitutive activation of ERK5, providing a direct link between ERK5, NFkappaB, and regulation of G2-M progression. We conclude that a novel ERK5-NFkappaB signaling pathway plays a key role in regulation of the G2-M progression.
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- 2007
18. Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo
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Hyung Joon Park, Richard D. Palmiter, Hyung-Wook Kim, Zhengui Xia, Won Seok Choi, Noah Sorscher, François Tronche, Expression des Gènes et comportement adaptatifs = Molecular Genetics, Neurophysiology and Behavior (NPS-15), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT, and Future Planning [NRF-2013R1A1A1059258, NRF-2014R1A1A2055836], NIH [ES012215, ES013696], National Institute of Child Health and Human Development [P30 HD02274], Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Aging ,Tyrosine 3-Monooxygenase ,Dopamine ,Parkinson's disease ,Dopamine Agents ,Substantia nigra ,Mitochondrial complex I ,Striatum ,Biology ,Motor Activity ,Article ,Levodopa ,chemistry.chemical_compound ,Mice ,Oxygen Consumption ,Antigens, Neoplasm ,Conditional gene knockout ,medicine ,Animals ,Dopamine neuron ,Mice, Knockout ,Dopamine Plasma Membrane Transport Proteins ,Electron Transport Complex I ,Dose-Response Relationship, Drug ,Pars compacta ,General Neuroscience ,MPTP ,Dopaminergic Neurons ,Dopaminergic ,Age Factors ,Mitochondria ,Substantia Nigra ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,nervous system ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Exploratory Behavior ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,Neuron ,Geriatrics and Gerontology ,Neuroscience ,Psychomotor Performance ,Developmental Biology ,medicine.drug ,Synaptosomes - Abstract
International audience; Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased alpha-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of alpha- synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.
- Published
- 2015
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19. p38 Map Kinase Mediates Bax Translocation in Nitric Oxide–Induced Apoptosis in Neurons
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Leena S. Patel, Michal Hetman, Yoshito Kinoshita, Stephen Larner, Zhengui Xia, Richard J. Youle, Richard S. Morrison, and Saadi Ghatan
- Subjects
p53 ,Nitroprusside ,Programmed cell death ,caspase ,Excitotoxicity ,Apoptosis ,medicine.disease_cause ,Nitric Oxide ,p38 Mitogen-Activated Protein Kinases ,Translocation, Genetic ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Bcl-2-associated X protein ,Proto-Oncogene Proteins ,medicine ,Tumor Cells, Cultured ,Humans ,ASK1 ,Caspase ,030304 developmental biology ,bcl-2-Associated X Protein ,Cerebral Cortex ,Neurons ,0303 health sciences ,biology ,Kinase ,neuronal cell death ,Cell Biology ,Molecular biology ,Cell biology ,mitochondria ,Proto-Oncogene Proteins c-bcl-2 ,Mitogen-activated protein kinase ,Caspases ,biology.protein ,Original Article ,Mitogen-Activated Protein Kinases ,excitotoxicity ,030217 neurology & neurosurgery - Abstract
Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.
- Published
- 2000
20. Conditional Deletion of ERK5 MAP Kinase in the Nervous System Impairs Pheromone Information Processing and Pheromone-Evoked Behaviors
- Author
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Zhengui Xia, Daniel R. Storm, and Junhui Zou
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Nervous system ,Male ,medicine.medical_specialty ,MAPK7 ,lcsh:Medicine ,Biology ,Nervous System ,Pheromones ,03 medical and health sciences ,Gene Knockout Techniques ,Mice ,Sexual Behavior, Animal ,0302 clinical medicine ,Neural Stem Cells ,Internal medicine ,medicine ,Animals ,lcsh:Science ,Testosterone ,Mitogen-Activated Protein Kinase 7 ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Behavior, Animal ,Aggression ,lcsh:R ,Organ Size ,Olfactory Bulb ,Neural stem cell ,Olfactory bulb ,Endocrinology ,medicine.anatomical_structure ,Sex pheromone ,Pheromone ,lcsh:Q ,Female ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery ,Gene Deletion ,Research Article - Abstract
ERK5 MAP kinase is highly expressed in the developing nervous system but absent in most regions of the adult brain. It has been implicated in regulating the development of the main olfactory bulb and in odor discrimination. However, whether it plays an essential role in pheromone-based behavior has not been established. Here we report that conditional deletion of the Mapk7 gene which encodes ERK5 in mice in neural stem cells impairs several pheromone-mediated behaviors including aggression and mating in male mice. These deficits were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression. Using mouse urine as a natural pheromone-containing solution, we provide evidence that the behavior impairment was associated with defects in the detection of closely related pheromones as well as with changes in their innate preference for pheromones related to sexual and reproductive activities. We conclude that expression of ERK5 during development is critical for pheromone response and associated animal behavior in adult mice.
- Published
- 2013
21. Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition.
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Giurisato, Emanuele, Qiuping Xu, Lonardi, Silvia, Telfer, Brian, Russo, Ilaria, Pearson, Adam, Finegan, Katherine G., Wenbin Wang, Jinhua Wang, Gray, Nathanael S., Vermi, William, Zhengui Xia, and Tournier, Cathy
- Subjects
PROTEIN kinases ,STAT proteins ,MACROPHAGES ,TUMOR growth ,DISEASE progression ,CANCER immunotherapy - Abstract
Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression. [ABSTRACT FROM AUTHOR]
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- 2018
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22. Inducible and Targeted Deletion of the ERK5 MAP Kinase in Adult Neurogenic Regions Impairs Adult Neurogenesis in the Olfactory Bulb and Several Forms of Olfactory Behavior
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Zhengui Xia, Yung Wei Pan, Chay T. Kuo, and Daniel R. Storm
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Male ,Anatomy and Physiology ,Mouse ,lcsh:Medicine ,Pheromones ,Behavioral Neuroscience ,Mice ,0302 clinical medicine ,Habituation ,lcsh:Science ,Neurons ,0303 health sciences ,Multidisciplinary ,Microscopy, Confocal ,Neurogenesis ,Brain ,Animal Models ,Phenotype ,Olfactory Bulb ,Sensory Systems ,Smell ,medicine.anatomical_structure ,Olfactory Learning ,Signal transduction ,Research Article ,Signal Transduction ,Subventricular zone ,Endocrine System ,Mice, Transgenic ,Biology ,Signaling Pathways ,03 medical and health sciences ,Model Organisms ,medicine ,Animals ,Olfactory memory ,Mitogen-Activated Protein Kinase 7 ,030304 developmental biology ,Olfactory System ,Endocrine Physiology ,lcsh:R ,Olfactory bulb ,Tamoxifen ,nervous system ,Bromodeoxyuridine ,Immunology ,Odorants ,lcsh:Q ,Molecular Neuroscience ,Neuroscience ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Although adult-born neurons in the subventricular zone (SVZ) and olfactory bulb (OB) have been extensively characterized at the cellular level, their functional impact on olfactory behavior is still highly controversial with many conflicting results reported in the literature. Furthermore, signaling mechanisms regulating adult SVZ/OB neurogenesis are not well defined. Here we report that inducible and targeted deletion of erk5, a MAP kinase selectively expressed in the adult neurogenic regions of the adult brain, impairs adult neurogenesis in the SVZ and OB of transgenic mice. Although erk5 deletion had no effect on olfactory discrimination among discrete odorants in the habituation/dishabituation assay, it reduced short-term olfactory memory as well as detection sensitivity to odorants and pheromones including those evoking aggression and fear. Furthermore, these mice show impaired acquisition of odor-cued associative olfactory learning, a novel phenotype that had not been previously linked to adult neurogenesis. These data suggest that ERK5 MAP kinase is a critical kinase signaling pathway regulating adult neurogenesis in the SVZ/OB, and provide strong evidence supporting a functional role for adult neurogenesis in several distinct forms of olfactory behavior.
- Published
- 2012
23. The maintenance of established remote contextual fear memory requires ERK5 MAP kinase and ongoing adult neurogenesis in the hippocampus
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Zhengui Xia, Yung Wei Pan, and Daniel R. Storm
- Subjects
Male ,Memory, Long-Term ,Genotype ,Neurogenesis ,Hippocampus ,lcsh:Medicine ,Contextual fear ,Biology ,Hippocampal formation ,Signaling Pathways ,Neurological Signaling ,Behavioral Neuroscience ,Mice ,03 medical and health sciences ,Learning and Memory ,0302 clinical medicine ,Developmental Neuroscience ,Memory ,Molecular Cell Biology ,Conditioning, Psychological ,Gene Order ,Animals ,lcsh:Science ,Mitogen-Activated Protein Kinase 7 ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Dentate gyrus ,lcsh:R ,Fear ,Remote memory ,Signaling in Selected Disciplines ,Animal Cognition ,Mitogen-activated protein kinase ,biology.protein ,Female ,Memory consolidation ,lcsh:Q ,Molecular Neuroscience ,Neuroscience ,Gene Deletion ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction - Abstract
Adult neurogenesis in the dentate gyrus of the hippocampal formation has been implicated in several forms of hippocampus-dependent memory. However, its role in the persistence of remote memory is unknown. Furthermore, whether the hippocampus plays a role in maintaining remote contextual memories is controversial. Here we used an inducible gene-specific approach for conditional deletion of erk5 in the adult neurogenic regions of the mouse brain to specifically impair adult neurogenesis. The erk5 gene was conditionally deleted under three different experimental conditions: prior to training for contextual fear, 6 days after training, or 5 weeks after training, We present evidence that remote memory was impaired under all three conditions. These data demonstrate that ongoing adult neurogenesis is required both for the initial establishment and the continued maintenance of remote contextual fear memory, even after the remote memory has transferred into extra-hippocampal regions of the brain 5 weeks after training.
- Published
- 2012
24. Adult type 3 adenylyl cyclase-deficient mice are obese
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Aaron S. Nudelman, Guy C.-K. Chan, Trongha X. Phan, Daniel R. Storm, Zhenshan Wang, Vicky Li, and Zhengui Xia
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Leptin ,Male ,medicine.medical_specialty ,Period (gene) ,Hypothalamus ,Adipose tissue ,lcsh:Medicine ,Biology ,Diabetes and Endocrinology/Obesity ,Adenylyl cyclase ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Sex Factors ,0302 clinical medicine ,Internal medicine ,Adipocytes ,Cyclic AMP ,medicine ,Animals ,Lipolysis ,Obesity ,lcsh:Science ,030304 developmental biology ,Pharmacology ,Neurons ,2. Zero hunger ,0303 health sciences ,Polymorphism, Genetic ,Multidisciplinary ,Body Weight ,lcsh:R ,Wild type ,medicine.disease ,Endocrinology ,Adipose Tissue ,chemistry ,Female ,lcsh:Q ,Neuroscience/Neurobiology of Disease and Regeneration ,030217 neurology & neurosurgery ,Research Article ,Adenylyl Cyclases - Abstract
Background A recent study of obesity in Swedish men found that polymorphisms in the type 3 adenylyl cyclase (AC3) are associated with obesity, suggesting the interesting possibility that AC3 may play a role in weight control. Therefore, we examined the weight of AC3 mice over an extended period of time. Methodology/Principal Findings We discovered that AC3−/− mice become obese as they age. Adult male AC3−/− mice are about 40% heavier than wild type male mice while female AC3−/− are 70% heavier. The additional weight of AC3−/− mice is due to increased fat mass and larger adipocytes. Before the onset of obesity, young AC3−/− mice exhibit reduced physical activity, increased food consumption, and leptin insensitivity. Surprisingly, the obesity of AC3−/− mice is not due to a loss of AC3 from white adipose and a decrease in lipolysis. Conclusions/Significance We conclude that mice lacking AC3 exhibit obesity that is apparently caused by low locomotor activity, hyperphagia, and leptin insensitivity. The presence of AC3 in primary cilia of neurons of the hypothalamus suggests that cAMP signals generated by AC3 in the hypothalamus may play a critical role in regulation of body weight.
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- 2009
25. ERK5 MAP kinase regulates neurogenin1 during cortical neurogenesis
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Chris Englund, Xin Duan, Junhui Zou, Guo Li Ming, Lidong Liu, Zhengui Xia, Yung Wei Pan, Glen M. Abel, Robert F. Hevner, Yupeng Wang, and Paige Cundiff
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MAPK/ERK pathway ,Transcription, Genetic ,MAP Kinase Signaling System ,Neurogenesis ,Recombinant Fusion Proteins ,lcsh:Medicine ,Nerve Tissue Proteins ,Biology ,Nestin ,03 medical and health sciences ,0302 clinical medicine ,Intermediate Filament Proteins ,Transcription (biology) ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,Phosphorylation ,lcsh:Science ,Molecular Biology ,Transcription factor ,Cells, Cultured ,Mitogen-Activated Protein Kinase 7 ,030304 developmental biology ,Neurons ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Kinase ,Stem Cells ,lcsh:R ,Gene Expression Regulation, Developmental ,Cell Biology ,Rats ,Cell biology ,Enzyme Activation ,Mitogen-activated protein kinase ,biology.protein ,lcsh:Q ,030217 neurology & neurosurgery ,Research Article ,Developmental Biology ,Neuroscience - Abstract
The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors.
- Published
- 2009
26. p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription
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Zhengui Xia and Beibei Cai
- Subjects
Cancer Research ,Sodium arsenite ,Arsenites ,Pyridines ,p38 mitogen-activated protein kinases ,Clinical Biochemistry ,Pharmaceutical Science ,Apoptosis ,Calcium-Calmodulin-Dependent Protein Kinase Kinase ,Models, Biological ,PC12 Cells ,p38 Mitogen-Activated Protein Kinases ,Article ,chemistry.chemical_compound ,Enzyme activator ,RNA interference ,Animals ,Pharmacology ,biology ,Biochemistry (medical) ,Forkhead Box Protein O3 ,Imidazoles ,JNK Mitogen-Activated Protein Kinases ,Forkhead Transcription Factors ,Cell Biology ,Molecular biology ,Sodium Compounds ,Transport protein ,Cell biology ,Rats ,Up-Regulation ,Enzyme Activation ,Protein Transport ,chemistry ,Mitogen-activated protein kinase ,biology.protein ,Phosphorylation ,RNA Interference - Abstract
Sodium arsenite induces apoptosis in PC12 cells by activating the stress-activated p38 MAP kinase and the pro-apoptotic Bcl-2 family protein Bim(EL). However, the relationship between p38 and Bim(EL) in this apoptosis has not been fully defined. Here, we report that sodium arsenite stimulates the protein expression and promoter activity of Bim(EL) in a p38-dependent manner. Sodium arsenite also caused nuclear translocation of FOXO3a, indicative of FOXO3a activation. Addition of a p38 inhibitor prevented FOXO3a nuclear translocation. RNAi knock down of FOXO3a inhibited Bim promoter activity, Bim(EL) protein expression, and arsenite-induced apoptosis. Our data identify p38 activation of FOXO3a and subsequent induction of Bim(EL) expression as a novel apoptotic mechanism. Together with our previous finding that Bim(EL) is phosphorylated and activated by p38, these results demonstrate that p38 induces apoptosis by regulating Bim(EL) at both the transcriptional and post-translational levels.
- Published
- 2008
27. ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons
- Author
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Jane E. Cavanaugh, Zixu Mao, Zhengui Xia, Yupeng Wang, Lidong Liu, and Hiroyuki Sakagami
- Subjects
Mef2 ,Cell Survival ,Nerve Tissue Proteins ,Mitogen-activated protein kinase kinase ,MAP Kinase Kinase 5 ,Transfection ,Rats, Sprague-Dawley ,Neurotrophic factors ,Genes, Reporter ,Gene expression ,Premovement neuronal activity ,Animals ,Mitogen-Activated Protein Kinase 7 ,Brain-derived neurotrophic factor ,Cerebral Cortex ,Mitogen-Activated Protein Kinase Kinases ,Neurons ,Multidisciplinary ,biology ,MEF2 Transcription Factors ,Brain-Derived Neurotrophic Factor ,Gene Expression Regulation, Developmental ,Biological Sciences ,Cell biology ,Rats ,DNA-Binding Proteins ,nervous system ,Myogenic Regulatory Factors ,biology.protein ,Signal transduction ,Mitogen-Activated Protein Kinases ,Neurotrophin ,Signal Transduction ,Transcription Factors - Abstract
Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family whose biological function in the CNS has not been defined. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in cortical neurons, ERK5 is activated only by NTs. Here, we report that ERK5 expression is high in the brain during early embryonic development but declines as the brain matures to almost undetectable levels by postnatal day (P) 49. Interestingly, expression of a dominant-negative ERK5 blocked brain-derived neurotrophic factor protection against trophic withdrawal in primary cortical neurons cultured from embryonic day (E) 17 but not P0. Furthermore, expression of a dominant-negative ERK5 induced apoptosis in E17 but not P0 cortical neurons maintained in the presence of serum. We also present evidence that ERK5 protection of E17 cortical neurons may be mediated through myocyte enhancer factor 2-induced gene expression. These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons.
- Published
- 2003
28. Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation
- Author
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Elizabeth A. Thiele, Jun Xing, Zhengui Xia, Jon M. Kornhauser, and Michael E. Greenberg
- Subjects
MAPK/ERK pathway ,Transcription, Genetic ,p38 mitogen-activated protein kinases ,Becaplermin ,Mitogen-activated protein kinase kinase ,CREB ,PC12 Cells ,p38 Mitogen-Activated Protein Kinases ,Ribosomal s6 kinase ,Mice ,Serine ,Animals ,Humans ,Nerve Growth Factors ,Phosphorylation ,Protein kinase A ,Cyclic AMP Response Element-Binding Protein ,Molecular Biology ,Cell Growth and Development ,Genes, Immediate-Early ,Platelet-Derived Growth Factor ,MAP kinase kinase kinase ,biology ,Ribosomal Protein S6 Kinases ,Cyclin-dependent kinase 2 ,Cell Biology ,Proto-Oncogene Proteins c-sis ,Molecular biology ,Rats ,Enzyme Activation ,COS Cells ,Calcium-Calmodulin-Dependent Protein Kinases ,biology.protein ,Mitogen-Activated Protein Kinases - Abstract
The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.
- Published
- 1998
29. Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK-Dependent Mechanism
- Author
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Henryk Dudek, Zhengui Xia, Cindy K. Miranti, and Michael E. Greenberg
- Subjects
MAPK/ERK pathway ,Transcriptional Activation ,Serum Response Factor ,Transcription, Genetic ,Glutamic Acid ,Nerve Tissue Proteins ,Biology ,Transfection ,Receptors, N-Methyl-D-Aspartate ,Proto-Oncogene Proteins ,Serum response factor ,Animals ,Transcription factor ,Genes, Immediate-Early ,Cells, Cultured ,ets-Domain Protein Elk-1 ,Regulation of gene expression ,Neurons ,Binding Sites ,General Neuroscience ,Glutamate receptor ,Nuclear Proteins ,Receptor Protein-Tyrosine Kinases ,Articles ,Receptor, EphA8 ,Serum Response Element ,Recombinant Proteins ,Cell biology ,Rats ,DNA-Binding Proteins ,Biochemistry ,Calcium-Calmodulin-Dependent Protein Kinases ,Trans-Activators ,NMDA receptor ,Calcium ,Immediate early gene ,Transcription Factors - Abstract
The regulation of gene expression by neurotransmitters is likely to play a key role in neuroplasticity both during development and in the adult animal. Therefore, it is important to determine the mechanisms of neuronal gene regulation to understand fully the mechanisms of learning, memory, and other long-term adaptive changes in neurons. The neurotransmitter glutamate stimulates rapid and transient induction of many genes, including the c-fosproto-oncogene. The c-fospromoter contains several critical regulatory elements, including the serum response element (SRE), that mediate glutamate-induced transcription in neurons; however, the mechanism by which the SRE functions in neurons has not been defined. In this study, we sought to identify transcription factors that mediate glutamate induction of transcription through the SRE in cortical neurons and to elucidate the mechanism(s) of transcriptional activation by these factors. To facilitate this analysis, we developed an improved calcium phosphate coprecipitation procedure to transiently introduce DNA into primary neurons, both efficiently and consistently. Using this protocol, we demonstrate that the transcription factors serum response factor (SRF) and Elk-1 can mediate glutamate induction of transcription through the SRE in cortical neurons. There are at least two distinct pathways by which glutamate signals through the SRE: an SRF-dependent pathway that can operate in the absence of Elk and an Elk-dependent pathway. Activation of the Elk-dependent pathway of transcription seems to require phosphorylation of Elk-1 by extracellular signal-regulated kinases (ERKs), providing evidence for a physiological function of ERKs in glutamate signaling in neurons. Taken together, these findings suggest that SRF, Elk, and ERKs may have important roles in neuroplasticity.
- Published
- 1996
30. Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice
- Author
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Richard D. Palmiter, Enrique C. Villacres, Michele L. Simmons, Charles Chavkin, Steven A. Thomas, Zhengui Xia, Daniel R. Storm, and Zhi Liang Wu
- Subjects
medicine.medical_specialty ,Gs alpha subunit ,Long-Term Potentiation ,Restriction Mapping ,Biology ,Hippocampus ,ADCY10 ,Adenylyl cyclase ,chemistry.chemical_compound ,Mice ,Mice, Neurologic Mutants ,Internal medicine ,Cerebellum ,medicine ,Cyclic AMP ,Animals ,Learning ,Evoked Potentials ,Cells, Cultured ,Cerebral Cortex ,Neurons ,ADCY6 ,Genomic Library ,Multidisciplinary ,ADCY9 ,Brain ,Long-term potentiation ,ADCY3 ,Cell biology ,Kinetics ,Endocrinology ,chemistry ,Synaptic plasticity ,Calcium ,Research Article ,Adenylyl Cyclases ,Brain Stem - Abstract
The murine Ca(2+)-stimulated adenylyl cyclase (type I) (EC 4.6.1.1), which is expressed predominantly in brain, was inactivated by targeted mutagenesis. Ca(2+)-stimulated adenylyl cyclase activity was reduced 40-60% in the hippocampus, neocortex, and cerebellum. Long-term potentiation in the CA1 region of the hippocampus from mutants was perturbed relative to controls. Both the initial slope and maximum extent of changes in synaptic response were reduced. Although mutant mice learned to find a hidden platform in the Morris water task normally, they did not display a preference for the region where the platform had been when it was removed. These results indicate that disruption of the gene for the type I adenylyl cyclase produces changes in behavior and that the cAMP signal transduction pathway may play an important role in synaptic plasticity.
- Published
- 1995
31. Inducible Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis in the Olfactory Bulb and Improves Olfactory Function.
- Author
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Wenbin Wang, Song Lu, Tan Li, Yung-Wei Pan, Junhui Zou, Abel, Glen M., Lihong Xu, Storm, Daniel R., and Zhengui Xia
- Subjects
MITOGEN-activated protein kinases ,DEVELOPMENTAL neurobiology ,OLFACTORY bulb ,LABORATORY mice ,NEUROPHYSIOLOGY - Abstract
Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function andhave more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse.
- Author
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Yu, Alfred K., Lanying Song, Murray, Karl D., van der List, Deborah, Chao Sun, Yan Shen, Zhengui Xia, and Cortopassi, Gino A.
- Published
- 2015
- Full Text
- View/download PDF
33. Genetic Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis and Extends Hippocampus-Dependent Long-Term Memory.
- Author
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Wenbin Wang, Yung-Wei Pan, Junhui Zou, Tan Li, Abel, Glen M., Palmiter, Richard D., Storm, Daniel R., and Zhengui Xia
- Subjects
MITOGEN-activated protein kinases ,DEVELOPMENTAL neurobiology ,HIPPOCAMPUS (Brain) ,LONG-term memory ,CELLULAR signal transduction ,LEARNING ,LABORATORY mice - Abstract
Recent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. We recently reported that the conditional and targeted knock-out of ERK5 MAP kinase in adult neurogenic regions of the mouse brain attenuates adult neurogenesis in the hippocampus and disrupts several forms of hippocampus-dependent memory. Here, we developed a gain-of-function knock-in mouse model to specifically activate endogenous ERK5 in the neurogenic regions of the adult brain. Were port that the selective and targeted activation of ERK5 increases adult neurogenesis in the dentate gyrus by enhancing cell survival, neuronal differentiation, and dendritic complexity. Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
34. Stimulation of Electro-Olfactogram Responses in the Main Olfactory Epithelia by Airflow Depends on the Type 3 Adenylyl Cyclase.
- Author
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Xuanmao Chen, Zhengui Xia, and Storm, Daniel R.
- Subjects
- *
EPITHELIAL cells , *ADENYLATE cyclase , *OLFACTORY cortex , *SENSORY neurons , *ORGANELLES , *SMELL , *AIR flow - Abstract
Cilia of olfactory sensory neurons are the primary sensory organelles for olfaction. The detection of odorants by the main olfactory epithelium (MOE) depends on coupling of odorant receptors to the type 3 adenylyl cyclase (AC3) in olfactory cilia. We monitored the effect of airflow on electro-olfactogram (EOG) responses and found that the MOE of mice can sense mechanical forces generated by airflow. The airflow-sensitive EOG response in the MOE was attenuated when cAMP was increased by odorants or by forskolin suggesting a common mechanism for airflow and odorant detection. In addition, the sensitivity to airflow was significantly impaired in the MOE from AC3-/- mice. We conclude that AC3 in the MOE is required for detecting the mechanical force of airflow, which in turn may regulate odorant perception during sniffing. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
35. Targeted Deletion of ERK5 MAP Kinase in the Developing Nervous System Impairs Development of GABAergic Interneurons in the Main Olfactory Bulb and Behavioral Discrimination between Structurally Similar Odorants.
- Author
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Junhui Zou, Yung-Wei Pan, Zhenshan Wang, Shih-Yu Chang, Wenbin Wang, Xin Wang, Tournier, Cathy, Storm, Daniel R., and Zhengui Xia
- Subjects
MITOGEN-activated protein kinases ,NERVOUS system development ,NEURONS ,CELL culture ,NEURAL stem cells ,LABORATORY mice ,CELLULAR signal transduction - Abstract
ERK5 MAP kinase is highly expressed in the developing nervous system and has been implicated in promoting the survival of immature neurons in culture. However, its role in the development and function of the mammalian nervous system has not been established in vivo. Here, we report that conditional deletion of the erk5 gene in mouse neural stem cells during development reduces the number of GABAergic interneurons in the main olfactory bulb (OB). Our data suggest that this is due to a decrease in proliferation and an increase in apoptosis in the subventricular zone and rostral migratory stream of ERK5 mutant mice. Interestingly,ERK5mutant mice have smaller OB and are impaired in odor discrimination between structurally similar odorants. We conclude that ERK5 is a novel signaling pathway regulating developmental OB neurogenesis and olfactory behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
36. ERK5 MAP Kinase Regulates Neurogenin1 during Cortical Neurogenesis.
- Author
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Cundiff, Paige, Lidong Liu, Yupeng Wang, Junhui Zou, Yung-Wei Pan, Abel, Glen, Xin Duan, Guo-li Ming, Englund, Chris, Hevner, Robert, and Zhengui Xia
- Subjects
DEVELOPMENTAL neurobiology ,FOCAL adhesion kinase ,TRANSCRIPTION factors ,PHOSPHORYLATION ,NEUROGENETICS ,GENETIC mutation ,CHEMICAL reactions ,PHOSPHORYLASES ,PLANT phosphorylation ,GENETICS ,NEUROSCIENCES - Abstract
The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basichelix- loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
37. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP[sup+], or paraquat.
- Author
-
Won-Seok Choi, Kruse, Shane E., PaImiter, Richard D., and Zhengui Xia
- Subjects
MITOCHONDRIAL pathology ,DOPAMINERGIC neurons ,LABORATORY rats ,MESENCEPHALON ,NEURONS ,ROTENONE - Abstract
Inhibition of mitochondrial complex 115 one of the leading hypoth- eses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit re- quired for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP[sup+], or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP[sup+], or paraquat is independent of complex I inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
38. Brain-derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte-enhancer factor 2C through an ERK1/2-RSK2 signaling cascade.
- Author
-
Yupeng Wang, Lidong Liu, and Zhengui Xia
- Subjects
NEUROTROPHINS ,MUSCLE cells ,NEURONS ,ALANINE ,PHOSPHORYLATION ,PROTEIN kinases - Abstract
Neurotrophin activation of myocyte-enhancer factor (MEF) 2C is one of the strongest pro-survival signaling pathways in developing neurons. To date, neurotrophin stimulation of MEF2C has been largely attributed to its direct phosphorylation by extracellular signal-regulated kinase (ERK) 5. Because MEF2C is not directly phosphorylated by ERK1/2 in vitro, it is generally assumed that the ERK1/2 signaling cascade does not regulate MEF2C. Surprisingly, we discovered that ERK1/2 are required for both the transcriptional and neuroprotective activity of MEF2C in cortical neurons stimulated by brain-derived neurotrophic factor. ERK1/2 stimulation of MEF2C is mediated by p90 ribosomal S6 kinase 2 (RSK2), a Ser/Thr protein kinase downstream of ERK1/2. RSK2 strongly phosphorylates purified recombinant MEF2C protein in vitro. Furthermore, RSK2 can directly phosphorylate MEF2C on S192, a consensus RSK2-phosphorylation site located in the transactivation domain of MEF2C. Substitution of S192 with a non-phosphorylatable alanine diminishes both the transcriptional and neuroprotective activity of MEF2C to an extent similar to mutation on S387, an established activating phosphorylation site. Together, our data identifies ERK1/2-RSK2 signaling as a novel mechanism by which neurotrophins activate MEF2C and promote neuronal survival. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
39. Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate.
- Author
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Lidong Liu, Cundiff, Paige, Abel, Glen, Yupeng Wang, Faigle, Roland, Sakagami, Hiroyuki, Mei Xu, and Zhengui Xia
- Subjects
NEURONS ,NEUROGLIA ,NEURAL circuitry ,NERVE tissue ,APOPTOSIS ,NERVOUS system - Abstract
Multipotent cortical progenitor cells differentiate into neurons and glial cells during development; however, mechanisms governing the specification of progenitors to a neuronal fate are not well understood. Although both extrinsic and intrinsic factors regulate this process, little is known about kinase signaling mechanisms that direct neuronal fate. Here, we report that extracellular signal-regulated kinase (ERK) 5 is expressed and active in proliferating cortical progenitors. Lentiviral gene delivery of a dominant negative ERK5 or dominant negative MAP kinase kinase 5 reduced the number of neurons generated from rat cortical progenitor cells in culture, whereas constitutive activation of ERK5 increased the production of neurons. Furthermore, when cortical progenitor cells were treated with ciliary neurotrophic factor, which induces precocious glial differentiation, ERK5 activation still promoted neuronal fate while suppressing glial differentiation. Our data also indicate that ERK5 does not directly regulate proliferation or apoptosis of cultured cortical progenitors. We conclude that ERK5 is necessary and sufficient to stimulate the generation of neurons from cortical progenitors. These results suggest a previously uncharacterized function for ERK5 signaling during brain development and raise the interesting possibility that extrinsic factors may instruct cortical progenitors to become neurons by activating the ERK5 pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
40. Basic Fibroblast Growth Factor Protects against Rotenone- Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases ½ and Phosphatidylinositol-3 Kinase Pathways.
- Author
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Shih-Ling Hsuan, Klintworth, Heather M., and Zhengui Xia
- Subjects
PARKINSON'S disease ,NEURODEGENERATION ,ROTENONE ,LABORATORY rats ,CELL death ,GROWTH factors - Abstract
Administration of rotenone to rats reproduces many features of Parkinson's disease, including dopaminergic neuron degeneration, and provides a useful model to study the pathogenesis of Parkinson's disease. However, the cell death mechanisms induced by rotenone and potential neuroprotective mechanisms against rotenone are not well defined. Here we report that rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells is attenuated by pretreatment with several growth factors, most notably basic fibroblast growth factor (bFGF). bFGF activated both extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3-kinase) pathways in SH-SY5Y cells. Ectopic activation of ERK1/2 or PI3-kinase protected against rotenone, whereas inhibition of either pathway attenuated bFGF protection. Reducing the expression of the proapoptotic protein Bcl-2-associated death protein (BAD) by small interfering RNA rendered SH-SY5Y cells resistant to rotenone, implicating BAD in rotenone-induced cell death. Interestingly, bFGF induced a long-lasting phosphorylation of BAD at serine 112, suggesting BAD inactivation through the ERK1/2 signaling pathway. Moreover, primary cultured dopaminergic neurons from mesencephalon were more sensitive to rotenone-induced cell death than nondopaminergic neurons in the same culture. The loss of dopaminergic neurons was blocked by bFGF, an inhibition dependent on ERK1/2 and PI3-kinase signaling. These data suggest that rotenone-induced dopaminergic cell death requires BAD and identify bFGF and its activation of ERK1/2 and PI3-kinase signaling pathways as novel intervention strategies to block cell death in the rotenone model of Parkinson's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
41. Cyclin-Dependent Kinase 5 Mediates Neurotoxin-Induced Degradation of the Transcription Factor Myocyte Enhancer Factor 2.
- Author
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Xiaoli Tang, Xuemin Wang, Xiaoming Gong, Ming Tong, Park, David, Zhengui Xia, and Zixu Mao
- Subjects
PHOSPHORYLATION ,CHEMICAL reactions ,TRANSCRIPTION factors ,PROTEIN kinases ,NEUROTOXICOLOGY ,NERVOUS system ,APOPTOSIS ,CELL death - Abstract
Regulation of the process of neuronal death plays a central role both during development of the CNS and in adult brain. The transcription factor myocyte enhancer factor 2 (MEF2) plays a critical role in neuronal survival. Cyclin-dependent kinase 5 (Cdk5) mediates neurotoxic effects by phosphorylating and inhibiting MEF2. How Cdk5-dependent phosphorylation reduces MEF2 transactivation activity remained unknown. Here, we demonstrate a novel mechanism by which Cdk5, in conjunction with caspase, inhibits MEF2. Using primary cerebellar granule neuron as a model, our investigation reveals that neurotoxicity induces destabilization of MEF2s in neurons. Destabilization of MEF2 is caused by an increase in caspase-dependent cleavage of MEF2. This cleavage event requires nuclear activation of Cdk5 activity. Phosphorylation by Cdk5 alone is sufficient to promote degradation of MEF2A and MEF2D by caspase-3. In contrast to MEF2A and MEF2D, MEF2C is not phosphorylated by Cdk5 after glutamate exposure and, therefore, resistant to neurotoxin-induced caspase-dependent degradation. Consistently, blocking Cdk5 or enhancing MEF2 reduced toxin-induced apoptosis. These findings define an important regulatory mechanism that for the first time links prodeath activities of Cdk5 and caspase. The convergence of Cdk5 phosphorylation-dependent caspase-mediated degradation of nuclear survival factors exemplified by MEF2 may represent a general process applicable to the regulation of other survival factors under diverse neurotoxic conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
42. The role of calmodulin as a signal integrator for synaptic plasticity.
- Author
-
Zhengui Xia and Storm, Daniel R.
- Subjects
- *
CALMODULIN , *SYNAPSES , *BRAIN , *NEUROPLASTICITY , *MENTAL depression - Abstract
Excitatory synapses in the brain show several forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which are initiated by increases in intracellular Ca2+ that are generated through NMDA (N-methyl-D-aspartate) receptors or voltage-sensitive Ca2+ channels. LTP depends on the coordinated regulation of an ensemble of enzymes, including Ca2+/calmodulin-dependent protein kinase II, adenylyl cyclase 1 and 8, and calcineurin, all of which are stimulated by calmodulin, a Ca2+-binding protein. In this review, we discuss the hypothesis that calmodulin is a central integrator of synaptic plasticity and that its unique regulatory properties allow the integration of several forms of signal transduction that are required for LTP and LTD. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
43. Rotenone-Induced Apoptosis Is Mediated By p38 And JNK MAP Kinases In Human Dopaminergic SH-SY5Y Cells.
- Author
-
Newhouse, Kathleen, Shih-Ling Hsuan, Chang, Sandra H., Beibei Cai, Yupeng Wang, and Zhengui Xia
- Subjects
ROTENONE ,ANIMAL models in research ,PARKINSON'S disease ,MITOGEN-activated protein kinases ,DOPAMINERGIC neurons ,APOPTOSIS - Abstract
Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson’s disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
44. A Novel Role For Serum Response Factor in Neuronal Survival.
- Author
-
Chang, Sandra H., Poser, Steve, and Zhengui Xia
- Subjects
NEUROTROPHINS ,NEURAL development ,APOPTOSIS ,NEURONS ,GENETIC transcription ,GENE expression - Abstract
Recent studies indicate that neuroprotection afforded by brain-derived neurotrophic factor (BDNF) is mediated by extracellular signalregulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K). However, the mechanisms by which ERK and PI3K exert neuroprotection are not completely understood. Because ERK1/2 and PI3K both stimulate serum response element (SRE)-mediated gene expression, and serum response factor (SRF) is indispensable for SRE-mediated transcription, we investigated whether SRF contributes to ERK1/2 and PI3K neuroprotection. To accomplish this goal, we used an established experimental paradigm in which BDNF protects postnatal cortical neurons against both trophic deprivation and camptothecin-induced DNA damage. BDNF protection against camptothecin is mediated primarily by ERK1/2 activation, whereas its protection against trophic deprivation is mainly through stimulation of the PI3K pathway (Hetman et al., 1999). Here we demonstrate that expression of a wild-type SRF is sufficient to protect postnatal cortical neurons against camptothecin or trophic deprivation. Expression of a dominant-negative SRF partially reversed BDNF neuroprotection against both apoptotic insults. Moreover, the dominant-negative SRF inhibited neuroprotection against trophic withdrawal afforded by expression of a constitutive active PI3K. In addition, protection against camptothecin by expression of constitutive active mitogen-activated protein kinase kinase 1, an upstream kinase that activates ERK1/2, was also blocked by expression of the dominant-negative SRF. These data suggest that SRF is both necessary and sufficient for BDNF neuroprotection of cortical neurons against trophic deprivation and DNA damage. Our data provide a direct demonstration of a biological function of SRF in neurons and a novel downstream neuroprotective mechanism common to both ERK1/2 and PI3K pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
45. Chlorpyrifos Induces Apoptosis in Rat Cortical Neurons that is Regulated by a Balance Between p38 and ERK/JNK MAP Kinases.
- Author
-
Caughlan, Anne, Newhouse, Kathleen, Uk Namgung, and Zhengui Xia
- Subjects
CHLORPYRIFOS ,APOPTOSIS ,CEREBRAL cortex ,LABORATORY rats ,FOCAL adhesion kinase ,ACETYLCHOLINESTERASE - Abstract
Chlorpyrifos, an acetylcholinesterase (AChE) inhibitor, is a widely used organophosphate pesticide. Recent concern has focused on its neurotoxicity that is not attributable to AChE inhibition. Here, we report that chlorpyrifos and chlorpyrifos-oxon, but not 3,5,6-trichloro-2-pyridinol (TCP; the breakdown product of chlorpyrifos and chlorpyrifos-oxon), induce apoptosis in primary cortical neurons cultured from embryonic day 17 or newborn rats. It is generally agreed that chlorpyrifos-oxon is approximately three orders of magnitude more potent than chlorpyrifos in inhibition of brain acetylcholinesterase activity. However, our data demonstrate that chlorpyrifos-oxon is only slightly more potent than chlorpyrifos in inducing apoptosis. This indicates that chlorpyrifos-induced apoptosis may occur independently of AChE inhibition, although AChE activity was not measured in this study. Furthermore, chlorpyrifos activates the ERK1/2 and p38 MAP kinases. Surprisingly, blocking ERK1/2 activation by the MEK inhibitor SL327 caused a small but statistically significant inhibition of apoptosis, while blocking p38 with SB202190 significantly accelerated apoptosis induced by chlorpyrifos. This suggests a pro- and anti-apoptotic role for ERK1/2 and p38, respectively. Although chlorpyrifos did not stimulate total JNK activity, it caused a sustained activation of a sub-pool of JNK in the nucleus and stimulated phosphorylation of c-Jun, a downstream target of JNK. Transient expression of a dominant negative c-Jun mutant inhibited chlorpyrifos-induced apoptosis, suggesting a role for JNK and JNK-mediated transcription in this cell death. Together, our data suggest apoptosis as a novel toxic endpoint of chlorpyrifos neurotoxicity in the brain that may be independent of AChE inhibition. Furthermore, activation of the ERK1/2 and JNK MAP kinases contributes to, while activation of the p38 MAP kinase counteracts chlorpyrifos-induced apoptosis in cortical neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
46. ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons.
- Author
-
Lidong Liu, Cavanaugh, Jane E., Yupeng Wang, Sakagami, Hiroyuki, Mao, Zixu, and Zhengui Xia
- Subjects
GENE expression ,PROTEIN kinases ,CENTRAL nervous system ,NEURONS - Abstract
Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family whose biological function in the CNS has not been defined. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in cortical neurons, ERK5 is activated only by NTs. Here, we report that ERK5 expression is high in the brain during early embryonic development but declines as the brain matures to almost undetectable levels by postnatal day (P) 49. Interestingly, expression of a dominant-negative ERK5 blocked brain-derived neurotrophic factor protection against trophic withdrawal in primary cortical neurons cultured from embryonic day (E) 17 but not PO. Furthermore, expression of a dominant-negative ERK5 induced apoptosis in E17 but not PO cortical neurons maintained in the presence of serum. We also present evidence that ERK5 protection of E17 cortical neurons may be mediated through myocyte enhancer factor 2-induced gene expression. These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
47. SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation.
- Author
-
Poser, Steve, Impey, Soren, Trinh, Kien, Zhengui Xia, and Storm, Daniel R.
- Subjects
CELL cycle ,GENETIC transcription ,MITOGENS ,CYCLINS ,GROWTH factors ,GENE expression - Abstract
Recent evidence indicates that phosphatidylinositol 3-kinase (PI3K) is a central regulator of mitosis, apoptosis and oncogenesis. Nevertheless, the mechanisms by which PI3K regulates proliferation are not well characterized. Mitogens stimulate entry into the cell cycle by inducing the expression of immediate early genes (IEGs) that in turn trigger the expression of G
1 cyclins. Here we describe a novel PI3K-regulated transcriptional cascade that is critical for mitogen regulation of the IEG, c-fos. We show that PI3K activates gene expression by transactivating SRF-dependent transcription independently of the previously described Rho and ETS TCF pathways. PI3K-stimulated cell cycle progression requires transactivation of SRF and expression of dominant-negative PI3K blocks mitogen-stimulated cell cycle progression. Furthermore, dominant-interfering SRF mutants attenuate mitogen-stimulated cell cycle progression, but are without effect on MEK-stimulated cell cycle entry. Moreover, expression of constitutively active SRF is sufficient for cell cycle entry. Thus, we delineate a novel SRF-dependent mitogenic cascade that is critical for PI3K- and growth factor-mediated cell cycle progression. [ABSTRACT FROM AUTHOR]- Published
- 2000
- Full Text
- View/download PDF
48. Alpha males win again.
- Author
-
DiRocco, Derek P. and Zhengui Xia
- Subjects
- *
DEVELOPMENTAL neurobiology , *PHEROMONES , *LABORATORY mice , *HIPPOCAMPUS (Brain) , *ANIMAL sexual behavior - Abstract
The article presents a study which suggests that neurogenesis induced in the female mouse brain by male pheromones governs the choice of dominant males as mates. The study reported data that links the preference of female mice for dominant males to pheromone-induced neurogenesis in the olfactory system and hippocampus.
- Published
- 2007
- Full Text
- View/download PDF
49. Activation of c-Jun N-Terminal Protein Kinase Is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Cell Apoptosis.
- Author
-
Heather Klintworth, Kathleen Newhouse, Tingting Li, Won-Seok Choi, Roland Faigle, and Zhengui Xia
- Subjects
PARKINSON'S disease ,DOPAMINERGIC neurons ,SUBSTANTIA nigra ,PHEOCHROMOCYTOMA - Abstract
Parkinsons disease (PD) is characterized by selective loss of dopaminergic neurons in the substantia nigra of the brain. Although the underlying causes are not well characterized, epidemiological studies suggest an elevated risk of PD with occupational pesticide exposure. Here, we utilized pheochromocytoma (PC) 12 and SH-SY5Y cells as well as rat primary cultured dopaminergic neurons to investigate mechanisms for dopaminergic cell death induced by paraquat and rotenone, pesticides that are used to model PD in rodents. Both paraquat and rotenone induce selective loss of dopaminergic neurons in primary cultures. We discovered that paraquat induces apoptosis in PC12 cells but not in SH-SY5Y cells, while rotenone exposure causes apoptosis in SH-SY5Y cells but not in PC12 cells. The selective ability of paraquat and rotenone to induce apoptosis in different cell lines correlates with their ability to activate c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinases. Furthermore, JNK and p38 are required for rotenone-induced apoptosis in SH-SY5Y cells (K. Newhouse et al., 2004, Toxicol. Sci. 79, 137–146) as well as primary neurons, and for paraquat-induced apoptosis in PC12 cells. However, JNK but not p38 plays a role in paraquat-induced loss of primary cultured dopaminergic neurons. Our data identify JNK activation as a common mechanism underlying dopaminergic cell death induced by both paraquat and rotenone in model cell lines and primary cultures. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
50. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model.
- Author
-
Won-Seok Choi, Palmiter, Richard D., and Zhengui Xia
- Subjects
- *
MITOCHONDRIAL pathology , *NEURODEGENERATION , *MICROTUBULES , *PARKINSON'S disease , *DOPAMINE - Abstract
Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson's disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4-/- mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotin-amide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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