43 results on '"Hansen DV"'
Search Results
2. Observed sea surface height and modeled dynamic height anomaly departures in the tropical Pacific Ocean: 1986-1989
- Author
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Maul, Ga, Bushell, Mh, Bravo, Nj, Hansen, Dv, Maul, Ga, Bushell, Mh, Bravo, Nj, and Hansen, Dv
- Abstract
Observations of sea surface height departure (SSH') from November 1986 through September 1989 in the tropical Pacific from the improved (T2) GEOSAT data set (Cheney et al., 1991) are compared with monthly mean dynamic height anomaly departure (Delta D') from the ''second reanalysis'' using the NOAA ocean analysis system (Ji et al., 1994, 1995). For comparisons, Delta D' is calculated by removing north-south tilt and bias as in SSH orbit error removal, giving standard deviation fields sigma(SSH') and sigma(Delta D') that quantitatively reproduce variability of the North Equatorial Current (NEC)/North Equatorial Countercurrent (NECC)/South Equatorial Current (SEC) system between El Nino and non-El Nino years. Hovmoller diagrams of SSH' and Delta D' variability at 110 degrees W, 140 degrees W, 170 degrees W, and 165 degrees E between 20 degrees S and 20 degrees N, and along the equator from 120 degrees E to 80 degrees W, display the amplitude and phase of the 1986-1987 El Nino-Southern Oscillation (ENSO) event as distinguished from the years following, with the NECC significantly weakened in 1987 as compared to 1988. Cross-correlations (r) between Delta D' and SSH' are highest near the Equator in the vicinity of the TOGA-TAO (Hayes et al., 1991; McPhaden, 1993) in situ mooring arrays, with values above r = 0.7 in much of the region +/- 7 degrees of the Equator across about half of the Pacific basin. Differences between Delta D' and SSH' are typically less than +/- 5 cm RMS in this same equatorial band, but there are two regions of differences in excess of +/- 15 cm RMS: off Central America and east of New Guinea. The reason for these large RMS differences is uncertain, but it is inferred from Lagrangian buoy data that intense eddy activity is unresolved in the model as compared to GEOSAT. For the 35 monthly realizations, the ensemble cross correlation r = 0.5 has +/- 7 cm RMS within +/- 15 degrees of the Equator, and peaks in 1988 with decay towards the end of the GEOS
- Published
- 1997
3. Rapid affinity optimization of an anti-TREM2 clinical lead antibody by cross-lineage immune repertoire mining.
- Author
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Hsiao YC, Wallweber HA, Alberstein RG, Lin Z, Du C, Etxeberria A, Aung T, Shang Y, Seshasayee D, Seeger F, Watkins AM, Hansen DV, Bohlen CJ, Hsu PL, and Hötzel I
- Subjects
- Animals, Humans, Rats, Membrane Glycoproteins immunology, B-Lymphocytes immunology, Immunoglobulin Heavy Chains immunology, Immunoglobulin Heavy Chains genetics, Epitopes immunology, Antibodies, Monoclonal immunology, Antibodies immunology, Complementarity Determining Regions immunology, Antibody Affinity immunology, Receptors, Immunologic immunology, Receptors, Immunologic genetics
- Abstract
We describe a process for rapid antibody affinity optimization by repertoire mining to identify clones across B cell clonal lineages based on convergent immune responses where antigen-specific clones with the same heavy (V
H ) and light chain germline segment pairs, or parallel lineages, bind a single epitope on the antigen. We use this convergence framework to mine unique and distinct VH lineages from rat anti-triggering receptor on myeloid cells 2 (TREM2) antibody repertoire datasets with high diversity in the third complementarity-determining loop region (CDR H3) to further affinity-optimize a high-affinity agonistic anti-TREM2 antibody while retaining critical functional properties. Structural analyses confirm a nearly identical binding mode of anti-TREM2 variants with subtle but significant structural differences in the binding interface. Parallel lineage repertoire mining is uniquely tailored to rationally explore the large CDR H3 sequence space in antibody repertoires and can be easily and generally applied to antibodies discovered in vivo., (© 2024. The Author(s).)- Published
- 2024
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4. Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.
- Author
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Etxeberria A, Shen YA, Vito S, Silverman SM, Imperio J, Lalehzadeh G, Soung AL, Du C, Xie L, Choy MK, Hsiao YC, Ngu H, Cho CH, Ghosh S, Novikova G, Rezzonico MG, Leahey R, Weber M, Gogineni A, Elstrott J, Xiong M, Greene JJ, Stark KL, Chan P, Roth GA, Adrian M, Li Q, Choi M, Wong WR, Sandoval W, Foreman O, Nugent AA, Friedman BA, Sadekar S, Hötzel I, Hansen DV, Chih B, Yuen TJ, Weimer RM, Easton A, Meilandt WJ, and Bohlen CJ
- Subjects
- Animals, Mice, Female, Male, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Antibodies pharmacology, Humans, Amyloid beta-Peptides metabolism, tau Proteins metabolism, Receptors, Immunologic agonists, Receptors, Immunologic metabolism, Receptors, Immunologic genetics, Membrane Glycoproteins agonists, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Multiple Sclerosis drug therapy, Multiple Sclerosis immunology, Microglia drug effects, Microglia metabolism
- Abstract
Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)
- Published
- 2024
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5. TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease.
- Author
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Lee SH, Rezzonico MG, Friedman BA, Huntley MH, Meilandt WJ, Pandey S, Chen YJ, Easton A, Modrusan Z, Hansen DV, Sheng M, and Bohlen CJ
- Subjects
- Alzheimer Disease immunology, Alzheimer Disease metabolism, Animals, Astrocytes immunology, Astrocytes metabolism, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oligodendroglia immunology, Oligodendroglia metabolism, Alzheimer Disease pathology, Amyloid chemistry, Astrocytes pathology, Membrane Glycoproteins physiology, Oligodendroglia pathology, Receptors, Immunologic physiology, T-Lymphocytes immunology, tau Proteins metabolism
- Abstract
Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA sequencing to broadly profile 13 cell types in three different mouse models of Alzheimer disease (AD), capturing the effects of tau-only, amyloid-only, or combined tau-amyloid pathology. We highlight microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes emerging differentially across disease models, and we determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are engaged in response to AD pathology, and how they are influenced by a key AD risk gene, Trem2., Competing Interests: Declaration of interests All authors are current or former employees of Genentech., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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6. Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology.
- Author
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Lee SH, Meilandt WJ, Xie L, Gandham VD, Ngu H, Barck KH, Rezzonico MG, Imperio J, Lalehzadeh G, Huntley MA, Stark KL, Foreman O, Carano RAD, Friedman BA, Sheng M, Easton A, Bohlen CJ, and Hansen DV
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Animals, Atrophy genetics, Atrophy metabolism, Atrophy pathology, Brain pathology, Disease Models, Animal, Membrane Glycoproteins genetics, Mice, Mice, Transgenic, Receptors, Immunologic genetics, tau Proteins genetics, Alzheimer Disease metabolism, Amyloid metabolism, Amyloid beta-Protein Precursor metabolism, Brain metabolism, Membrane Glycoproteins metabolism, Receptors, Immunologic metabolism, tau Proteins metabolism
- Abstract
Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2 deficiency in the pR5-183 mouse model expressing mutant tau alone or in TauPS2APP mice, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau., Competing Interests: Declaration of interests All authors are current or former employees of Genentech, Inc., with interests in developing novel therapeutic drugs for neurodegenerative diseases at the time of conducting this research., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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7. Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.
- Author
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Srinivasan K, Friedman BA, Etxeberria A, Huntley MA, van der Brug MP, Foreman O, Paw JS, Modrusan Z, Beach TG, Serrano GE, and Hansen DV
- Subjects
- Aged, Aged, 80 and over, Animals, Databases, Genetic, Female, Frontal Lobe pathology, Frozen Sections, Gene Expression Profiling, Genetic Predisposition to Disease, Heterografts, Humans, Male, Mice, Monocytes metabolism, Multiple Sclerosis pathology, Phenotype, Reproducibility of Results, Risk Factors, Temporal Lobe pathology, Alzheimer Disease genetics, Alzheimer Disease pathology, Cellular Senescence genetics, Microglia metabolism, Microglia pathology, Transcriptional Activation genetics
- Abstract
Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease., Competing Interests: Declaration of Interests T.G.B. and G.E.S. participated in this study under a contracted research agreement. All other authors are current or former employees of the pharmaceutical company Genentech, Inc.., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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8. Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model.
- Author
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Meilandt WJ, Ngu H, Gogineni A, Lalehzadeh G, Lee SH, Srinivasan K, Imperio J, Wu T, Weber M, Kruse AJ, Stark KL, Chan P, Kwong M, Modrusan Z, Friedman BA, Elstrott J, Foreman O, Easton A, Sheng M, and Hansen DV
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia pathology, Neurites pathology, Neurofilament Proteins cerebrospinal fluid, Plaque, Amyloid pathology, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Axons pathology, Dendritic Spines pathology, Membrane Glycoproteins genetics, Peptide Fragments metabolism, Plaque, Amyloid genetics, Receptors, Immunologic genetics, Trefoil Factor-1 metabolism
- Abstract
TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2
ko ) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2 -deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity. SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2 -deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in Trem2 -deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species., (Copyright © 2020 Meilandt et al.)- Published
- 2020
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9. Genome-Wide Analysis of Differential Gene Expression and Splicing in Excitatory Neurons and Interneuron Subtypes.
- Author
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Huntley MA, Srinivasan K, Friedman BA, Wang TM, Yee AX, Wang Y, Kaminker JS, Sheng M, Hansen DV, and Hanson JE
- Subjects
- Animals, Cells, Cultured, Female, Hippocampus metabolism, Male, Mice, Transgenic, Parvalbumins metabolism, RNA, Messenger metabolism, Somatostatin metabolism, Vasoactive Intestinal Peptide metabolism, Cerebral Cortex metabolism, Interneurons metabolism, Neurons metabolism, Transcriptome
- Abstract
Cortical circuit activity is shaped by the parvalbumin (PV) and somatostatin (SST) interneurons that inhibit principal excitatory (EXC) neurons and the vasoactive intestinal peptide (VIP) interneurons that suppress activation of other interneurons. To understand the molecular-genetic basis of functional specialization and identify potential drug targets specific to each neuron subtype, we performed a genome wide assessment of both gene expression and splicing across EXC, PV, SST and VIP neurons from male and female mouse brains. These results reveal numerous examples where neuron subtype-specific gene expression, as well as splice-isoform usage, can explain functional differences between neuron subtypes, including in presynaptic plasticity, postsynaptic receptor function, and synaptic connectivity specification. We provide a searchable web resource for exploring differential mRNA expression and splice form usage between excitatory, PV, SST, and VIP neurons (http://research-pub.gene.com/NeuronSubtypeTranscriptomes). This resource, combining a unique new dataset and novel application of analysis methods to multiple relevant datasets, identifies numerous potential drug targets for manipulating circuit function, reveals neuron subtype-specific roles for disease-linked genes, and is useful for understanding gene expression changes observed in human patient brains. SIGNIFICANCE STATEMENT Understanding the basis of functional specialization of neuron subtypes and identifying drug targets for manipulating circuit function requires comprehensive information on cell-type-specific transcriptional profiles. We sorted excitatory neurons and key inhibitory neuron subtypes from mouse brains and assessed differential mRNA expression. We used a genome-wide analysis which not only examined differential gene expression levels but could also detect differences in splice isoform usage. This analysis reveals numerous examples of neuron subtype-specific isoform usage with functional importance, identifies potential drug targets, and provides insight into the neuron subtypes involved in psychiatric disease. We also apply our analysis to two other relevant datasets for comparison, and provide a searchable website for convenient access to the resource., Competing Interests: Conflict-of-interest: all authors are current or former employees of Genentech., (Copyright © 2020 the authors.)
- Published
- 2020
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10. Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy.
- Author
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Wu T, Dejanovic B, Gandham VD, Gogineni A, Edmonds R, Schauer S, Srinivasan K, Huntley MA, Wang Y, Wang TM, Hedehus M, Barck KH, Stark M, Ngu H, Foreman O, Meilandt WJ, Elstrott J, Chang MC, Hansen DV, Carano RAD, Sheng M, and Hanson JE
- Subjects
- Alzheimer Disease genetics, Animals, Atrophy, Behavior, Animal, Biomarkers metabolism, Brain pathology, Complement C1q metabolism, Complement C3 cerebrospinal fluid, Complement C3 genetics, Disease Models, Animal, Female, Gene Deletion, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Nerve Degeneration genetics, Neurons metabolism, Neurons pathology, Plaque, Amyloid metabolism, Synapses metabolism, Alzheimer Disease immunology, Amyloidosis immunology, Complement C3 metabolism, Nerve Degeneration immunology, Tauopathies immunology
- Abstract
Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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11. Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease.
- Author
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Rathore N, Ramani SR, Pantua H, Payandeh J, Bhangale T, Wuster A, Kapoor M, Sun Y, Kapadia SB, Gonzalez L, Zarrin AA, Goate A, Hansen DV, Behrens TW, and Graham RR
- Subjects
- Amino Acid Substitution, Animals, Genetic Loci, Humans, Ligands, Membrane Glycoproteins chemistry, Mice, Models, Biological, Molecular Conformation, Protein Binding, Quantitative Trait Loci, Receptors, Immunologic chemistry, Structure-Activity Relationship, Alzheimer Disease genetics, Alzheimer Disease metabolism, Genetic Variation, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Receptors, Immunologic genetics, Receptors, Immunologic metabolism
- Abstract
Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer's disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer's disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence., Competing Interests: NR, SRR, HP, JP, TB, AW, YS, SBK, LG, AAZ, DVH, TWB and RRG were full-time employees at Genentech while the work was conducted. A patent has been submitted for this work.
- Published
- 2018
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12. Microglia in Alzheimer's disease.
- Author
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Hansen DV, Hanson JE, and Sheng M
- Subjects
- Animals, Brain metabolism, Brain pathology, Humans, Alzheimer Disease metabolism, Alzheimer Disease pathology, Microglia metabolism, Microglia pathology
- Abstract
Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology., (© 2018 Hansen et al.)
- Published
- 2018
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13. Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models.
- Author
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Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, Cao Y, Lee SH, Haddick PCG, Ngu H, Modrusan Z, Larson JL, Kaminker JS, van der Brug MP, and Hansen DV
- Subjects
- Alzheimer Disease metabolism, Animals, Disease Models, Animal, Humans, Mice, Alzheimer Disease genetics, Brain metabolism, Microglia metabolism
- Abstract
Microglia, the CNS-resident immune cells, play important roles in disease, but the spectrum of their possible activation states is not well understood. We derived co-regulated gene modules from transcriptional profiles of CNS myeloid cells of diverse mouse models, including new tauopathy model datasets. Using these modules to interpret single-cell data from an Alzheimer's disease (AD) model, we identified microglial subsets-distinct from previously reported "disease-associated microglia"-expressing interferon-related or proliferation modules. We then analyzed whole-tissue RNA profiles from human neurodegenerative diseases, including a new AD dataset. Correcting for altered cellular composition of AD tissue, we observed elevated expression of the neurodegeneration-related modules, but also modules not implicated using expression profiles from mouse models alone. We provide a searchable, interactive database for exploring gene expression in all these datasets (http://research-pub.gene.com/BrainMyeloidLandscape). Understanding the dimensions of CNS myeloid cell activation in human disease may reveal opportunities for therapeutic intervention., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
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14. Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation.
- Author
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Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, and Sheng M
- Subjects
- Animals, Granulins, Listeria monocytogenes immunology, Listeriosis immunology, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia metabolism, Progranulins, Transcriptome, Autophagy physiology, DNA-Binding Proteins metabolism, Intercellular Signaling Peptides and Proteins deficiency
- Abstract
Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying therapies for either FTD or NCL, in part because of a poor understanding of how mutations in genes such as GRN contribute to disease pathogenesis and neurodegeneration. By studying mice lacking progranulin (PGRN), the protein encoded by GRN , we discovered multiple lines of evidence that PGRN deficiency results in impairment of autophagy, a key cellular degradation pathway. PGRN-deficient mice are sensitive to Listeria monocytogenes because of deficits in xenophagy, a specialized form of autophagy that mediates clearance of intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and pathological forms of TDP-43 typically cleared by autophagy accumulate more rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel therapeutic target for GRN -associated NCL and FTD and highlight the emerging theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis spectrum of neurodegenerative disease., (© 2017 Chang et al.)
- Published
- 2017
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15. TREM2, Microglia, and Neurodegenerative Diseases.
- Author
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Yeh FL, Hansen DV, and Sheng M
- Subjects
- Aging genetics, Aging pathology, Alzheimer Disease epidemiology, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Amyloid beta-Peptides immunology, Animals, Humans, Membrane Glycoproteins genetics, Microglia pathology, Myeloid Cells pathology, Receptors, Immunologic genetics, United States epidemiology, Aging immunology, Alzheimer Disease immunology, Immunity, Innate, Membrane Glycoproteins immunology, Microglia immunology, Myeloid Cells immunology, Receptors, Immunologic immunology
- Abstract
Alzheimer's disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis. Recent studies have advanced our understanding of TREM2 biology and microglial activities in aging and neurodegenerative brains, providing new insights into TREM2 functions in amyloid plaque maintenance, microglial envelopment of plaque, microglia viability, and the identification of novel TREM2 ligands. Our increased understanding of TREM2 and microglia has opened new avenues for therapeutic intervention to delay or prevent the progression of AD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
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16. A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.
- Author
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Haddick PC, Larson JL, Rathore N, Bhangale TR, Phung QT, Srinivasan K, Hansen DV, Lill JR, Pericak-Vance MA, Haines J, Farrer LA, Kauwe JS, Schellenberg GD, Cruchaga C, Goate AM, Behrens TW, Watts RJ, Graham RR, Kaminker JS, and van der Brug M
- Subjects
- ADAM10 Protein metabolism, ADAM17 Protein metabolism, Aged, Aged, 80 and over, Alleles, Animals, Apolipoprotein E4 genetics, Astrocytes metabolism, CD4-Positive T-Lymphocytes metabolism, Coculture Techniques, Cohort Studies, Female, HEK293 Cells, Humans, Interleukin-6 metabolism, Male, Mice, Microglia metabolism, Recombinant Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Brain metabolism, Polymorphism, Single Nucleotide, Receptors, Interleukin-6 genetics, Receptors, Interleukin-6 metabolism
- Abstract
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.
- Published
- 2017
- Full Text
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17. Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury.
- Author
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Ertürk A, Mentz S, Stout EE, Hedehus M, Dominguez SL, Neumaier L, Krammer F, Llovera G, Srinivasan K, Hansen DV, Liesz A, Scearce-Levie KA, and Sheng M
- Subjects
- Animals, Brain pathology, CX3C Chemokine Receptor 1, Calcium-Binding Proteins metabolism, Chronic Disease, Dendritic Spines immunology, Dendritic Spines pathology, Dendritic Spines ultrastructure, Disease Models, Animal, Exploratory Behavior physiology, Female, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins metabolism, Motor Activity, Neurons metabolism, Neurons pathology, Psychomotor Performance physiology, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, Time Factors, Brain Injuries, Traumatic complications, Inflammation etiology, Nerve Degeneration diagnostic imaging, Nerve Degeneration etiology, Nerve Degeneration pathology, Recovery of Function physiology
- Abstract
Unlabelled: After traumatic brain injury (TBI), neurons surviving the initial insult can undergo chronic (secondary) degeneration via poorly understood mechanisms, resulting in long-term cognitive impairment. Although a neuroinflammatory response is promptly activated after TBI, it is unknown whether it has a significant role in chronic phases of TBI (>1 year after injury). Using a closed-head injury model of TBI in mice, we showed by MRI scans that TBI caused substantial degeneration at the lesion site within a few weeks and these did not expand significantly thereafter. However, chronic alterations in neurons were observed, with reduced dendritic spine density lasting >1 year after injury. In parallel, we found a long-lasting inflammatory response throughout the entire brain. Deletion of one allele of CX3CR1, a chemokine receptor, limited infiltration of peripheral immune cells and largely prevented the chronic degeneration of the injured brain and provided a better functional recovery in female, but not male, mice. Therefore, targeting persistent neuroinflammation presents a new therapeutic option to reduce chronic neurodegeneration., Significance Statement: Traumatic brain injury (TBI) often causes chronic neurological problems including epilepsy, neuropsychiatric disorders, and dementia through unknown mechanisms. Our study demonstrates that inflammatory cells invading the brain lead to secondary brain damage. Sex-specific amelioration of chronic neuroinflammation rescues the brain degeneration and results in improved motor functions. Therefore, this study pinpoints an effective therapeutic approach to preventing secondary complications after TBI., (Copyright © 2016 the authors 0270-6474/16/369962-14$15.00/0.)
- Published
- 2016
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18. Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement.
- Author
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Lee SH, Le Pichon CE, Adolfsson O, Gafner V, Pihlgren M, Lin H, Solanoy H, Brendza R, Ngu H, Foreman O, Chan R, Ernst JA, DiCara D, Hotzel I, Srinivasan K, Hansen DV, Atwal J, Lu Y, Bumbaca D, Pfeifer A, Watts RJ, Muhs A, Scearce-Levie K, and Ayalon G
- Subjects
- Alzheimer Disease pathology, Animals, Antibodies immunology, Brain metabolism, Brain pathology, Cells, Cultured, Coculture Techniques methods, Cytokines metabolism, Mice, Transgenic, Neurons metabolism, Alzheimer Disease metabolism, Microglia metabolism, tau Proteins metabolism
- Abstract
The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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19. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses.
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Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD, Appling LL, Borneo J, Poon C, Ho T, Cai F, Steiner P, van der Brug MP, Modrusan Z, Kaminker JS, and Hansen DV
- Subjects
- Adult, Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Astrocytes drug effects, Astrocytes pathology, Cerebellum drug effects, Cerebellum metabolism, Cerebellum pathology, Disease Models, Animal, Endotoxemia chemically induced, Endotoxemia metabolism, Endotoxemia pathology, Frontal Lobe drug effects, Frontal Lobe metabolism, Frontal Lobe pathology, Gene Expression Profiling, Gene Expression Regulation, Humans, Lipopolysaccharides pharmacology, Mice, Microglia drug effects, Microglia pathology, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurons drug effects, Neurons pathology, Organ Specificity, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Sequence Analysis, RNA, Alzheimer Disease genetics, Astrocytes metabolism, Endotoxemia genetics, Microglia metabolism, Neurons metabolism, Transcription, Genetic, Transcriptome
- Abstract
A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease.
- Published
- 2016
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20. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death.
- Author
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Wetzel-Smith MK, Hunkapiller J, Bhangale TR, Srinivasan K, Maloney JA, Atwal JK, Sa SM, Yaylaoglu MB, Foreman O, Ortmann W, Rathore N, Hansen DV, Tessier-Lavigne M, Mayeux R, Pericak-Vance M, Haines J, Farrer LA, Schellenberg GD, Goate A, Behrens TW, Cruchaga C, Watts RJ, and Graham RR
- Subjects
- Aged, Aged, 80 and over, Amyloid beta-Peptides, Animals, CA3 Region, Hippocampal cytology, Cell Death genetics, Female, Genetic Predisposition to Disease, Glutamic Acid, HEK293 Cells, Humans, Male, Mice, Netrin Receptors, Rats, Staurosporine, Alzheimer Disease genetics, Neurons metabolism, Receptors, Cell Surface genetics, Receptors, Nerve Growth Factor genetics
- Abstract
We have identified a rare coding mutation, T835M (rs137875858), in the UNC5C netrin receptor gene that segregated with disease in an autosomal dominant pattern in two families enriched for late-onset Alzheimer's disease and that was associated with disease across four large case-control cohorts (odds ratio = 2.15, Pmeta = 0.0095). T835M alters a conserved residue in the hinge region of UNC5C, and in vitro studies demonstrate that this mutation leads to increased cell death in human HEK293T cells and in rodent neurons. Furthermore, neurons expressing T835M UNC5C are more susceptible to cell death from multiple neurotoxic stimuli, including β-amyloid (Aβ), glutamate and staurosporine. On the basis of these data and the enriched hippocampal expression of UNC5C in the adult nervous system, we propose that one possible mechanism in which T835M UNC5C contributes to the risk of Alzheimer's disease is by increasing susceptibility to neuronal cell death, particularly in vulnerable regions of the Alzheimer's disease brain.
- Published
- 2014
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21. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences.
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Hansen DV, Lui JH, Flandin P, Yoshikawa K, Rubenstein JL, Alvarez-Buylla A, and Kriegstein AR
- Subjects
- Animals, Cell Differentiation, Cell Movement, Fetus, Humans, LIM-Homeodomain Proteins metabolism, Mice, Neocortex anatomy & histology, Nerve Tissue Proteins metabolism, Organ Culture Techniques, RNA, Messenger metabolism, Transcription Factors metabolism, Cerebral Ventricles cytology, GABAergic Neurons physiology, Gene Expression Regulation, Developmental physiology, Interneurons physiology, Multipotent Stem Cells physiology, Neocortex embryology
- Abstract
GABAergic cortical interneurons underlie the complexity of neural circuits and are particularly numerous and diverse in humans. In rodents, cortical interneurons originate in the subpallial ganglionic eminences, but their developmental origins in humans are controversial. We characterized the developing human ganglionic eminences and found that the subventricular zone (SVZ) expanded massively during the early second trimester, becoming densely populated with neural stem cells and intermediate progenitor cells. In contrast with the cortex, most stem cells in the ganglionic eminence SVZ did not maintain radial fibers or orientation. The medial ganglionic eminence exhibited unique patterns of progenitor cell organization and clustering, and markers revealed that the caudal ganglionic eminence generated a greater proportion of cortical interneurons in humans than in rodents. On the basis of labeling of newborn neurons in slice culture and mapping of proliferating interneuron progenitors, we conclude that the vast majority of human cortical interneurons are produced in the ganglionic eminences, including an enormous contribution from non-epithelial SVZ stem cells.
- Published
- 2013
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22. A high-resolution enhancer atlas of the developing telencephalon.
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Visel A, Taher L, Girgis H, May D, Golonzhka O, Hoch RV, McKinsey GL, Pattabiraman K, Silberberg SN, Blow MJ, Hansen DV, Nord AS, Akiyama JA, Holt A, Hosseini R, Phouanenavong S, Plajzer-Frick I, Shoukry M, Afzal V, Kaplan T, Kriegstein AR, Rubin EM, Ovcharenko I, Pennacchio LA, and Rubenstein JL
- Subjects
- Animals, Embryo, Mammalian metabolism, Fetus metabolism, Genome-Wide Association Study, Humans, Mice, Telencephalon embryology, Transcriptome, p300-CBP Transcription Factors metabolism, Enhancer Elements, Genetic, Telencephalon metabolism
- Abstract
The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. Though many of the genes required for its development have been identified, the distant-acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here, we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon. We identified more than 4,600 candidate embryonic forebrain enhancers and studied the in vivo activity of 329 of these sequences in transgenic mouse embryos. We generated serial sets of histological brain sections for 145 reproducible forebrain enhancers, resulting in a publicly accessible web-based data collection comprising more than 32,000 sections. We also used epigenomic analysis of human and mouse cortex tissue to directly compare the genome-wide enhancer architecture in these species. These data provide a primary resource for investigating gene regulatory mechanisms of telencephalon development and enable studies of the role of distant-acting enhancers in neurodevelopmental disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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23. Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex.
- Author
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LaMonica BE, Lui JH, Hansen DV, and Kriegstein AR
- Subjects
- Humans, Neocortex cytology, Neuroglia cytology, Spindle Apparatus
- Abstract
The human neocortex is increased in size and complexity as compared with most other species. Neocortical expansion has recently been attributed to protracted neurogenesis by outer radial glial cells in the outer subventricular zone, a region present in humans but not in rodents. The mechanisms of human outer radial glial cell generation are unknown, but are proposed to involve division of ventricular radial glial cells; neural stem cells present in all developing mammals. Here we show that human ventricular radial glial cells produce outer radial glial cells and seed formation of the outer subventricular zone via horizontal divisions, which occur more frequently in humans than in rodents. We further find that outer radial glial cell mitotic behaviour is cell intrinsic, and that the basal fibre, inherited by outer radial glial cells after ventricular radial glial division, determines cleavage angle. Our results suggest that altered regulation of mitotic spindle orientation increased outer radial glial cell number, and ultimately neuronal number, during human brain evolution.
- Published
- 2013
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24. Development and evolution of the human neocortex.
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Lui JH, Hansen DV, and Kriegstein AR
- Subjects
- Animals, Cell Movement, Humans, Neocortex cytology, Neocortex embryology, Neural Stem Cells cytology, Neurogenesis, Receptors, Notch metabolism, Signal Transduction, Biological Evolution, Neocortex physiology
- Abstract
The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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25. Deriving excitatory neurons of the neocortex from pluripotent stem cells.
- Author
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Hansen DV, Rubenstein JL, and Kriegstein AR
- Subjects
- Animals, Cell Differentiation physiology, Humans, Neocortex cytology, Neurons cytology, Pluripotent Stem Cells cytology, Excitatory Postsynaptic Potentials physiology, Neocortex physiology, Neurons physiology, Pluripotent Stem Cells physiology
- Abstract
The human cerebral cortex is an immensely complex structure that subserves critical functions that can be disrupted in developmental and degenerative disorders. Recent innovations in cellular reprogramming and differentiation techniques have provided new ways to study the cellular components of the cerebral cortex. Here, we discuss approaches to generate specific subtypes of excitatory cortical neurons from pluripotent stem cells. We review spatial and temporal aspects of cortical neuron specification that can guide efforts to produce excitatory neuron subtypes with increased resolution. Finally, we discuss distinguishing features of human cortical development and their translational ramifications for cortical stem cell technologies., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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26. Neurogenic radial glia in the outer subventricular zone of human neocortex.
- Author
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Hansen DV, Lui JH, Parker PR, and Kriegstein AR
- Subjects
- Animals, Cells, Cultured, Humans, Neurons cytology, Receptors, Notch antagonists & inhibitors, Signal Transduction, Stem Cells cytology, Cell Differentiation, Neocortex cytology, Neocortex embryology, Neurogenesis physiology, Neuroglia cytology
- Abstract
Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.
- Published
- 2010
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27. Cdc2 and Mos regulate Emi2 stability to promote the meiosis I-meiosis II transition.
- Author
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Tang W, Wu JQ, Guo Y, Hansen DV, Perry JA, Freel CD, Nutt L, Jackson PK, and Kornbluth S
- Subjects
- Animals, CDC2 Protein Kinase, Cell Movement, Cyclin B metabolism, Cyclin-Dependent Kinases, Endocytosis, HL-60 Cells, Humans, Leukocytes metabolism, Mice, Mice, Inbred C57BL, Models, Biological, Neutrophils metabolism, Proto-Oncogene Proteins c-mos metabolism, Cyclin B physiology, F-Box Proteins physiology, Gene Expression Regulation, Meiosis, Proto-Oncogene Proteins c-mos physiology
- Abstract
The transition of oocytes from meiosis I (MI) to meiosis II (MII) requires partial cyclin B degradation to allow MI exit without S phase entry. Rapid reaccumulation of cyclin B allows direct progression into MII, producing a cytostatic factor (CSF)-arrested egg. It has been reported that dampened translation of the anaphase-promoting complex (APC) inhibitor Emi2 at MI allows partial APC activation and MI exit. We have detected active Emi2 translation at MI and show that Emi2 levels in MI are mainly controlled by regulated degradation. Emi2 degradation in MI depends not on Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), but on Cdc2-mediated phosphorylation of multiple sites within Emi2. As in MII, this phosphorylation is antagonized by Mos-mediated recruitment of PP2A to Emi2. Higher Cdc2 kinase activity in MI than MII allows sufficient Emi2 phosphorylation to destabilize Emi2 in MI. At MI anaphase, APC-mediated degradation of cyclin B decreases Cdc2 activity, enabling Cdc2-mediated Emi2 phosphorylation to be successfully antagonized by Mos-mediated PP2A recruitment. These data suggest a model of APC autoinhibition mediated by stabilization of Emi2; Emi2 proteins accumulate at MI exit and inhibit APC activity sufficiently to prevent complete degradation of cyclin B, allowing MI exit while preventing interphase before MII entry.
- Published
- 2008
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28. Control of Emi2 activity and stability through Mos-mediated recruitment of PP2A.
- Author
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Wu JQ, Hansen DV, Guo Y, Wang MZ, Tang W, Freel CD, Tung JJ, Jackson PK, and Kornbluth S
- Subjects
- Amino Acid Sequence, Animals, F-Box Proteins genetics, Humans, Molecular Sequence Data, Phosphorylation, Proto-Oncogene Proteins c-mos genetics, Ribosomal Protein S6 Kinases metabolism, Signal Transduction, Xenopus, Xenopus Proteins genetics, F-Box Proteins metabolism, Meiosis, Ovum physiology, Phosphorylase Phosphatase metabolism, Proto-Oncogene Proteins c-mos metabolism, Xenopus Proteins metabolism
- Abstract
Before fertilization, vertebrate eggs are arrested in meiosis II by cytostatic factor (CSF), which holds the anaphase-promoting complex (APC) in an inactive state. It was recently reported that Mos, an integral component of CSF, acts in part by promoting the Rsk-mediated phosphorylation of the APC inhibitor Emi2/Erp1. We report here that Rsk phosphorylation of Emi2 promotes its interaction with the protein phosphatase PP2A. Emi2 residues adjacent to the Rsk phosphorylation site were important for PP2A binding. An Emi2 mutant that retained Rsk phosphorylation but lacked PP2A binding could not be modulated by Mos. PP2A bound to Emi2 acted on two distinct clusters of sites phosphorylated by Cdc2, one responsible for modulating its stability during CSF arrest and one that controls binding to the APC. These findings provide a molecular mechanism for Mos action in promoting CSF arrest and also define an unusual mechanism, whereby protein phosphorylation recruits a phosphatase for dephosphorylation of distinct sites phosphorylated by another kinase.
- Published
- 2007
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29. Emi2 at the crossroads: where CSF meets MPF.
- Author
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Hansen DV, Pomerening JR, Summers MK, Miller JJ, Ferrell JE Jr, and Jackson PK
- Subjects
- Amino Acid Sequence, Anaphase-Promoting Complex-Cyclosome, Animals, Cell Division physiology, F-Box Proteins antagonists & inhibitors, F-Box Proteins metabolism, Female, Maturation-Promoting Factor metabolism, Mesothelin, Mice, Molecular Sequence Data, Oocytes, Proto-Oncogene Proteins c-mos metabolism, Ubiquitin-Protein Ligase Complexes antagonists & inhibitors, Ubiquitin-Protein Ligase Complexes metabolism, Ubiquitin-Protein Ligase Complexes physiology, Xenopus Proteins antagonists & inhibitors, Xenopus Proteins metabolism, F-Box Proteins physiology, Maturation-Promoting Factor physiology, Proto-Oncogene Proteins c-mos physiology, Xenopus Proteins physiology
- Abstract
Vertebrate eggs arrest at metaphase of meiosis II due to an activity known as cytostatic factor (CSF). CSF antagonizes the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C), preventing cyclin B destruction and meiotic exit until fertilization occurs. A puzzling feature of CSF arrest is that APC/C inhibition is leaky. Ongoing cyclin B synthesis is counterbalanced by a limited amount of APC/C-mediated cyclin B destruction; thus, cyclin B/Cdc2 activity remains at steady state. How the APC/C can be slightly active toward cyclin B, and yet restrained from ubiquitinating cyclin B altogether, is unknown. Emi2/XErp1 is the critical CSF component directly responsible for APC/C inhibition during CSF arrest. Fertilization triggers the Ca2+-dependent destruction of Emi2, releasing the APC/C to ubiquitinate the full pool of cyclin B and initiate completion of meiosis. Previously, we showed that a phosphatase maintains Emi2's APC/C-inhibitory activity in CSF-arrested Xenopus egg extracts. Here, we demonstrate that phosphatase inhibition permits Emi2 phosphorylation at thr-545 and -551, which inactivates Emi2. Furthermore, we provide evidence that adding excess cyclin B to CSF extracts stimulates Cdc2 phosphorylation of these same residues, antagonizing Emi2-APC/C association. Our findings suggest a model wherein the pool of Emi2 acts analogously to a rheostat by integrating Cdc2 and phosphatase activities to prevent cyclin B overaccumulation and Cdc2 hyperactivity during the indefinite period of time between arrival at metaphase II and eventual fertilization. Finally, we propose that inactivation of Emi2 by Cdc2 permits mitotic progression during early embryonic cleavage cycles.
- Published
- 2007
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30. Translational unmasking of Emi2 directs cytostatic factor arrest in meiosis II.
- Author
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Tung JJ, Padmanabhan K, Hansen DV, Richter JD, and Jackson PK
- Subjects
- Animals, F-Box Proteins physiology, Female, Oocytes cytology, Oocytes metabolism, Rabbits, Xenopus, Xenopus Proteins genetics, Xenopus Proteins metabolism, F-Box Proteins genetics, F-Box Proteins metabolism, Meiosis genetics, Protein Biosynthesis physiology, Proto-Oncogene Proteins c-mos antagonists & inhibitors, Proto-Oncogene Proteins c-mos physiology, Xenopus Proteins antagonists & inhibitors, Xenopus Proteins physiology
- Abstract
Cytostatic factor (CSF) arrests unfertilized vertebrate eggs in metaphase of meiosis II by inhibiting the anaphase-promoting complex/cyclosome (APC/C) from mediating cyclin destruction. The APC/C inhibitor Emi2/XErp1 satisfies a number of historical criteria for the molecular identification of CSF, but the mechanism by which CSF is activated selectively in meiosis II is the remaining unexplained criterion. Here we provide an explanation by showing that Emi2 is expressed specifically in meiosis II through translational de-repression or "unmasking" of its mRNA. We find that Emi2 protein is undetectable in immature, G2/prophase-arrested Xenopus oocytes and accumulates approximately 90 minutes after germinal vesicle breakdown. The 3' untranslated region of Emi2 mRNA contains cytoplasmic polyadenylation elements that directly bind the CPEB protein and confer temporal regulation of Emi2 polyadenylation and translation. Our results demonstrate that cytoplasmic polyadenylation and translational unmasking of Emi2 directs meiosis II-specific CSF arrest.
- Published
- 2007
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31. Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis.
- Author
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Madgwick S, Hansen DV, Levasseur M, Jackson PK, and Jones KT
- Subjects
- Animals, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Differentiation physiology, Cell Nucleus metabolism, Cell Nucleus ultrastructure, Cyclin B1, Down-Regulation physiology, F-Box Proteins antagonists & inhibitors, F-Box Proteins genetics, Female, Metaphase physiology, Mice, Microtubules metabolism, Microtubules ultrastructure, Oligonucleotides, Antisense pharmacology, Oocytes ultrastructure, Spindle Apparatus metabolism, Spindle Apparatus ultrastructure, Cyclin B metabolism, Cytokinesis physiology, F-Box Proteins metabolism, Meiosis physiology, Oocytes metabolism, Oogenesis physiology
- Abstract
During interkinesis, a metaphase II (MetII) spindle is built immediately after the completion of meiosis I. Oocytes then remain MetII arrested until fertilization. In mouse, we find that early mitotic inhibitor 2 (Emi2), which is an anaphase-promoting complex inhibitor, is involved in both the establishment and the maintenance of MetII arrest. In MetII oocytes, Emi2 needs to be degraded for oocytes to exit meiosis, and such degradation, as visualized by fluorescent protein tagging, occurred tens of minutes ahead of cyclin B1. Emi2 antisense morpholino knockdown during oocyte maturation did not affect polar body (PB) extrusion. However, in interkinesis the central spindle microtubules from meiosis I persisted for a short time, and a MetII spindle failed to assemble. The chromatin in the oocyte quickly decondensed and a nucleus formed. All of these effects were caused by the essential role of Emi2 in stabilizing cyclin B1 after the first PB extrusion because in Emi2 knockdown oocytes a MetII spindle was recovered by Emi2 rescue or by expression of nondegradable cyclin B1 after meiosis I.
- Published
- 2006
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32. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor.
- Author
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Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL, Loktev A, and Jackson PK
- Subjects
- Amino Acid Motifs, Anaphase-Promoting Complex-Cyclosome, Antigens, CD, Binding, Competitive, Cadherins metabolism, Cadherins physiology, Cell Cycle Proteins metabolism, Cell Nucleus enzymology, Cell Nucleus metabolism, Conserved Sequence, F-Box Proteins metabolism, HeLa Cells, Humans, Interphase physiology, Protein Binding, Substrate Specificity, Cell Cycle Proteins physiology, Enzyme Inhibitors metabolism, F-Box Proteins physiology, Ubiquitin-Protein Ligase Complexes antagonists & inhibitors, Ubiquitin-Protein Ligase Complexes metabolism
- Abstract
The periodic destruction of mitotic cyclins is triggered by the activation of the anaphase-promoting complex/cyclosome (APC/C) in mitosis. Although the ability of the APC/C to recognize destruction box (D-box) substrates oscillates throughout the cell cycle, the mechanism regulating APC/C binding to D-box substrates remains unclear. Here, we show that the APC/C inhibitor Emi1 tightly binds both the APC/C and its Cdh1 activator, binds to the D-box receptor site on the APC/C(Cdh1), and competes with APC/C substrates for D-box binding. Emi1 itself contains a conserved C-terminal D-box, which provides APC/C-binding affinity, and a conserved zinc-binding region (ZBR), which antagonizes APC/C E3 ligase activity independent of tight APC binding. Mutation of the ZBR converts Emi1 into a D-box-dependent APC/C substrate. The identification of a direct Emi1-APC/C complex further explains how Emi1 functions as a stabilizing factor for cyclin accumulation and the need to destroy Emi1 for APC/C activation in mitosis. The combination of a degron/E3 recognition site and an anti-ligase function in Emi1 suggests a general model for how E3 substrates evolve to become pseudosubstrate inhibitors.
- Published
- 2006
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33. The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1.
- Author
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Eldridge AG, Loktev AV, Hansen DV, Verschuren EW, Reimann JD, and Jackson PK
- Subjects
- Anaphase-Promoting Complex-Cyclosome, Animals, Cell Cycle physiology, Cell Cycle Proteins pharmacology, Cell Line, F-Box Proteins, GTPase-Activating Proteins, HeLa Cells, Humans, Interphase, Models, Biological, Nuclear Proteins genetics, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, SKP Cullin F-Box Protein Ligases metabolism, Two-Hybrid System Techniques, Ubiquitin-Protein Ligase Complexes antagonists & inhibitors, Xenopus, Polo-Like Kinase 1, Anaphase physiology, Cell Cycle Proteins metabolism, Cyclin A metabolism, Nuclear Proteins metabolism, Ubiquitin-Protein Ligase Complexes metabolism
- Abstract
The anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 controls progression to S phase and mitosis by stabilizing key APC/C ubiquitination substrates, including cyclin A. Examining Emi1 binding proteins, we identified the Evi5 oncogene as a regulator of Emi1 accumulation. Evi5 antagonizes SCF(betaTrCP)-dependent Emi1 ubiquitination and destruction by binding to a site adjacent to Emi1's DSGxxS degron and blocking both degron phosphorylation by Polo-like kinases and subsequent betaTrCP binding. Thus, Evi5 functions as a stabilizing factor maintaining Emi1 levels in S/G2 phase. Evi5 protein accumulates in early G1 following Plk1 destruction and is degraded in a Plk1- and ubiquitin-dependent manner in early mitosis. Ablation of Evi5 induces precocious degradation of Emi1 by the Plk/SCF(betaTrCP) pathway, causing premature APC/C activation; cyclin destruction; cell-cycle arrest; centrosome overduplication; and, finally, mitotic catastrophe. We propose that the balance of Evi5 and Polo-like kinase activities determines the timely accumulation of Emi1 and cyclin, ensuring mitotic fidelity.
- Published
- 2006
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34. CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit.
- Author
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Hansen DV, Tung JJ, and Jackson PK
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Cell Cycle Proteins metabolism, Cyclin B genetics, Fertilization physiology, Oocytes enzymology, Phosphoric Monoester Hydrolases physiology, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Xenopus, Calcium-Calmodulin-Dependent Protein Kinases physiology, Cell Cycle Proteins physiology, F-Box Proteins metabolism, Meiosis physiology, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins c-mos metabolism, Xenopus Proteins metabolism, Xenopus Proteins physiology
- Abstract
In vertebrate meiosis, unfertilized eggs are arrested in metaphase II by cytostatic factor (CSF), which is required to maintain mitotic cyclin-dependent kinase activity. Fertilization triggers a transient increase in cytosolic free Ca(2+), which leads to CSF inactivation and ubiquitin-dependent cyclin destruction through the anaphase promoting complex or cyclosome (APC/C). The Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and the Polo-like kinase Plx1 are essential factors for Ca(2+)-induced meiotic exit, but the critical targets of these kinases were unknown. The APC/C inhibitor Emi2 or XErp1 has recently been characterized as a pivotal CSF component, required to maintain metaphase II arrest and rapidly destroyed in response to Ca(2+) signaling through phosphorylation by Plx1 and ubiquitination by the SCF(betaTrCP) complex. An important question is how the increase in free Ca(2+) targets Plx1 activity toward Emi2. Here, we demonstrate that CaMKII is required for Ca(2+)-induced Emi2 destruction, and that CaMKII functions as a "priming kinase," directly phosphorylating Emi2 at a specific motif to induce a strong interaction with the Polo Box domain of Plx1. We show that the strict requirement for CaMKII to phosphorylate Emi2 is a specific feature of CSF arrest, and we also use phosphatase inhibitors to demonstrate an additional mode of Emi2 inactivation independent of its destruction. We firmly establish the CSF component Emi2 as the first-known critical and direct target of CaMKII in CSF release, providing a detailed molecular mechanism explaining how CaMKII and Plx1 coordinately direct APC/C activation and meiotic exit upon fertilization.
- Published
- 2006
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35. A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus eggs.
- Author
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Tung JJ, Hansen DV, Ban KH, Loktev AV, Summers MK, Adler JR 3rd, and Jackson PK
- Subjects
- Anaphase physiology, Anaphase-Promoting Complex-Cyclosome, Animals, Calcium Signaling, Cell Cycle Proteins genetics, Cell Cycle Proteins immunology, Cross Reactions, Cyclin B metabolism, F-Box Proteins genetics, F-Box Proteins immunology, Female, In Vitro Techniques, Meiosis physiology, Molecular Sequence Data, Oocytes growth & development, Xenopus genetics, Xenopus growth & development, Xenopus Proteins genetics, Xenopus Proteins immunology, Cell Cycle Proteins metabolism, F-Box Proteins metabolism, Oocytes cytology, Oocytes metabolism, Proto-Oncogene Proteins c-mos metabolism, Ubiquitin-Protein Ligase Complexes antagonists & inhibitors, Xenopus metabolism, Xenopus Proteins metabolism
- Abstract
Unfertilized vertebrate eggs are arrested in metaphase of meiosis II with high cyclin B/Cdc2 activity to prevent parthenogenesis. Until fertilization, exit from metaphase is blocked by an activity called cytostatic factor (CSF), which stabilizes cyclin B by inhibiting the anaphase-promoting complex (APC) ubiquitin ligase. The APC inhibitor early mitotic inhibitor 1 (Emi1) was recently found to be required for maintenance of CSF arrest. We show here that exogenous Emi1 is unstable in CSF-arrested Xenopus eggs and is destroyed by the SCF(betaTrCP) ubiquitin ligase, suggesting that endogenous Emi1, an apparent 44-kDa protein, requires a stabilizing factor. However, anti-Emi1 antibodies crossreact with native Emi2/Erp1/FBXO43, a homolog of Emi1 and conserved APC inhibitor. Emi2 is stable in CSF-arrested eggs, is sufficient to prevent CSF release, and is rapidly degraded in a Polo-like kinase 1-dependent manner in response to calcium-mediated egg activation. These results identify Emi2 as a candidate CSF maintenance protein.
- Published
- 2005
- Full Text
- View/download PDF
36. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1.
- Author
-
Hansen DV, Loktev AV, Ban KH, and Jackson PK
- Subjects
- Anaphase, Anaphase-Promoting Complex-Cyclosome, Animals, Cell Cycle Proteins genetics, Cell Line, Cell Polarity, Enzyme Activation, F-Box Proteins, Humans, Mitosis, Phosphorylation, Phosphoserine metabolism, Protein Binding, Protein Kinases genetics, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins genetics, Spindle Apparatus metabolism, Time Factors, Ubiquitin metabolism, Xenopus Proteins, Xenopus laevis, Polo-Like Kinase 1, Cell Cycle Proteins metabolism, Protein Kinases metabolism, Proto-Oncogene Proteins metabolism, SKP Cullin F-Box Protein Ligases metabolism, Ubiquitin-Protein Ligase Complexes antagonists & inhibitors, Ubiquitin-Protein Ligase Complexes metabolism
- Abstract
Progression through mitosis requires activation of cyclin B/Cdk1 and its downstream targets, including Polo-like kinase and the anaphase-promoting complex (APC), the ubiquitin ligase directing degradation of cyclins A and B. Recent evidence shows that APC activation requires destruction of the APC inhibitor Emi1. In prophase, phosphorylation of Emi1 generates a D-pS-G-X-X-pS degron to recruit the SCF(betaTrCP) ubiquitin ligase, causing Emi1 destruction and allowing progression beyond prometaphase, but the kinases directing this phosphorylation remain undefined. We show here that the polo-like kinase Plk1 is strictly required for Emi1 destruction and that overexpression of Plk1 is sufficient to trigger Emi1 destruction. Plk1 stimulates Emi1 phosphorylation, betaTrCP binding, and ubiquitination in vitro and cyclin B/Cdk1 enhances these effects. Plk1 binds to Emi1 in mitosis and the two proteins colocalize on the mitotic spindle poles, suggesting that Plk1 may spatially control Emi1 destruction. These data support the hypothesis that Plk1 activates the APC by directing the SCF-dependent destruction of Emi1 in prophase.
- Published
- 2004
- Full Text
- View/download PDF
37. Control of the centriole and centrosome cycles by ubiquitination enzymes.
- Author
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Hansen DV, Hsu JY, Kaiser BK, Jackson PK, and Eldridge AG
- Subjects
- Animals, Cell Cycle physiology, Hydrolysis, Ligases metabolism, Neoplasms ultrastructure, Centrioles physiology, Centrosome physiology, Ligases physiology, Ubiquitin metabolism
- Published
- 2002
- Full Text
- View/download PDF
38. Phylogenetic analysis of Hoxa 11 sequences reveals absence of transposable elements, conservation of transcription factor binding sites, and suggests antisense coding function.
- Author
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Bodenmiller DM, Baxter CS, Hansen DV, and Potter SS
- Subjects
- Animals, Base Sequence, Binding Sites, Chickens, Conserved Sequence, Humans, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Proto-Oncogene Proteins, Repetitive Sequences, Nucleic Acid, Sequence Alignment, Sequence Analysis, DNA, DNA Transposable Elements, DNA, Antisense physiology, Homeodomain Proteins genetics, Oncogene Proteins genetics, Phylogeny
- Abstract
Nine thousand and eighty-eight base pairs of the chicken Hoxa 11 gene, including 8470 bases 5' of the translation start site were sequenced, and the characteristics of the upstream sequence investigated. Consistent with previous findings that middle repetitive elements are rare in the HoxA cluster, no repetitive elements were found other than simple oligonucleotide repeats. Multiple and pairwise alignments of the chicken upstream sequence with its human and mouse orthologs revealed multiple regions of 80% or higher homology across species. For the chicken, these regions were separated by sequences with no significant homology to human, mouse, or in most cases any other Genbank sequences. Selective clustering of transcription factor binding motifs was found to occur within the conserved homologous regions, suggesting evolutionary conservation of critical regulatory sequences. Of particular interest, seven conserved Cdx binding sites were found in the Hoxa 11 promoter, suggesting regulation by a non-clustered Caudal homeobox gene. Previous analysis of the mouse and human Hoxa 11 genes found a conserved antisense transcript, of unknown function. The chicken Hoxa 11 antisense strand included a conserved open reading frame capable of encoding 168 amino acids. Comparison of this region in mouse and chicken showed seven insertion/deletions, with each a multiple of three bases, thereby preserving open reading frame.
- Published
- 2002
- Full Text
- View/download PDF
39. Selenium regulates expression in rat liver of genes for proteins involved in iron metabolism.
- Author
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Christensen MJ, Olsen CA, Hansen DV, and Ballif BC
- Subjects
- Animals, Biomarkers, Diet, Glutathione Peroxidase metabolism, Glutathione Transferase metabolism, Immunoblotting, In Situ Hybridization, Liver drug effects, Male, RNA, Messenger biosynthesis, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Selenium deficiency, Transferrin metabolism, Gene Expression Regulation, Enzymologic drug effects, Iron metabolism, Liver enzymology, Selenium pharmacology
- Abstract
Suppression subtractive hybridization analysis in our laboratory recently revealed that transferrin mRNA may be elevated in Sedeficient rat liver. In this work, we compared expression in rat liver of genes for transferrin, transferrin receptor, ferritin light and heavy chains, and iron-regulatory proteins 1 and 2 in Se adequacy and deficiency. Weanling male Sprague-Dawley rats were fed Torula yeast diets supplemented with 0 or 0.15 microg Se/kg diet as sodium selenite for 15 wk. Activity of cellular glutathione peroxidase was virtually abolished in Se-deficient rat liver, whereas activity of glutathione S-transferase was 43% higher than in Se-adequate liver. There were no differences in hematocrit, hemoglobin, or liver iron content. To examine differential gene expression, we used a multiplex relative reverse transcriptase-polymerase chain reaction method. Three of the six genes examined showed modest but consistent upregulation in Se deficiency. Transferrin mRNA was 30% more abundant in Se-deficient than in Se-adequate liver. For the transferrin receptor, the difference was 32%, and for iron regulatory protein 1, it was 63%. No consistent differences were observed for iron regulatory protein 2 or for ferritin light or heavy chain. These findings suggest a possible role for dietary Se in moderating iron metabolism.
- Published
- 2000
- Full Text
- View/download PDF
40. Strontium-89 therapy for painful osseous metastatic prostate and breast cancer.
- Author
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Hansen DV, Holmes ER, Catton G, Thorne DA, Chadwick DH, and Schmutz DA
- Subjects
- Clinical Trials, Phase III as Topic, Female, Humans, Male, Bone Neoplasms radiotherapy, Bone Neoplasms secondary, Breast Neoplasms pathology, Palliative Care, Prostatic Neoplasms pathology, Strontium Radioisotopes therapeutic use
- Abstract
Strontium-89 chloride is a radiopharmaceutical that localizes to actively forming new bone, such as metastatic bone lesions from prostate and breast cancer. It provides effective systemic endo-osseous local radiation therapy to these painful lesions. Strontium-89 will soon be available to physicians in the United States for use in the palliative management of metastatic bone pain.
- Published
- 1993
41. Hospital privileges for family physicians.
- Author
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Hansen DV, Sundwall DN, and Kane RL
- Subjects
- Evaluation Studies as Topic, Hospital Administration, United States, Family Practice, Hospitals statistics & numerical data, Institutional Practice
- Published
- 1977
42. Hospital privileges for family physicians: a comparative study between the New England states and the intermountain states.
- Author
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Sundwall DN and Hansen DV
- Subjects
- New England, United States, Medical Staff Privileges trends, Medical Staff, Hospital, Physician's Role, Physicians, Family, Role
- Published
- 1979
43. Oceanographic observations of the 1982 warming of the tropical eastern pacific.
- Author
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Halpern D, Hayes SP, Leetmaa A, Hansen DV, and Philander SG
- Abstract
Moored current meter, sea level, hydrographic, and surface drifter measurements show the large changes that took place in the eastern tropical Pacific during the onset of the warm episode of 1982. In August the near-surface flow at 0 degrees , 110 degrees W reversed direction to eastward. By October the sea surface temperature in the equatorial zone increased by 5 degrees Celsius above the long-term monthly mean value, sea level rose by 22 centimeters at the Galápagos Islands, and the thermocline was displaced downward by 50 to 70 meters along the equator and the South American coast.
- Published
- 1983
- Full Text
- View/download PDF
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