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The enzyme dUTPase has an essential role in maintaining genomic integrity. In mouse, nuclear and mitochondrial isoforms of the enzyme have been described. Here we present the isoform-specific mRNA expression levels in different murine organs during development using RT-qPCR. In this study, we analyzed organs of 14.5-day embryos and of postnatal 2-, 4-, 10-week- and 13-month-old mice. We demonstrate organ-, sex- and developmental stage-specific differences in the mRNA expression levels of both isoforms. We found high mRNA expression level of the nuclear isoform in the embryo brain, and the expression level remained relatively high in the adult brain as well. This was surprising, since dUTPase is known to play an important role in proliferating cells, and mass production of neural cells is completed by adulthood. Thus, we investigated the pattern of the dUTPase protein expression specifically in the adult brain with immunostaining and found that dUTPase is present in the germinative zones, the subventricular and the subgranular zones, where neurogenesis occurs and in the rostral migratory stream where neuroblasts migrate to the olfactory bulb. These novel findings suggest that dUTPase may have a role in cell differentiation and indicate that accurate dTTP biosynthesis can be vital, especially in neurogenesis. [ABSTRACT FROM AUTHOR]

Proper embryonic development depends on the timely progression of a genetic program. One of the key mechanisms for achieving precise control of developmental timing is to use gene expression oscillations. In this Review, we examine how gene expression oscillations encode temporal information during vertebrate embryonic development by discussing the gene expression oscillations occurring during somitogenesis, neurogenesis, myogenesis and pancreas development. These oscillations play important but varied physiological functions in different contexts. Oscillations control the period of somite formation during somitogenesis, whereas they regulate the proliferation-to-differentiation switch of stem cells and progenitor cells during neurogenesis, myogenesis and pancreas development. We describe the similarities and differences of the expression pattern in space (i.e. whether oscillations are synchronous or asynchronous across neighboring cells) and in time (i.e. different time scales) of mammalian Hes/zebrafish Her genes and their targets in different tissues. We further summarize experimental evidence for the functional role of their oscillations. Finally, we discuss the outstanding questions for future research. [ABSTRACT FROM AUTHOR]

Thyroid hormones (TH) play critical roles during nervous system development and patients carrying coding variants of MCT8 (monocarboxylate transporter 8) or THRA (thyroid hormone receptor alpha) present a spectrum of neurological phenotypes resulting from perturbed local TH action during early brain development. Recently, human cerebral organoids (hCOs) emerged as powerful in vitro tools for disease modelling recapitulating key aspects of early human cortex development. To begin exploring prospects of this model for thyroid research, we performed a detailed characterization of the spatiotemporal expression of MCT8 and THRA in developing hCOs. Immunostaining showed MCT8 membrane expression in neuronal progenitor cell types including early neuroepithelial cells, radial glia cells (RGCs), intermediate progenitors and outer RGCs. In addition, we detected robust MCT8 protein expression in deep layer and upper layer neurons. Spatiotemporal SLC16A2 mRNA expression, detected by fluorescent in situ hybridization (FISH), was highly concordant with MCT8 protein expression across cortical cell layers. FISH detected THRA mRNA expression already in neuroepithelium before the onset of neurogenesis. THRA mRNA expression remained low in the ventricular zone, increased in the subventricular zone whereas strong THRA expression was observed in excitatory neurons. In combination with a robust up-regulation of known T3 response genes following T3 treatment, these observations show that hCOs provide a promising and experimentally tractable model to probe local TH action during human cortical neurogenesis and eventually to model the consequences of impaired TH function for early cortex development. [ABSTRACT FROM AUTHOR]

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible formanifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the genetic effects of commonly used radiofrequency on the amniocytes of pregnant women by examining the changes in the expression of genes related to signal transduction and neurogenesis induced by electromagnetic fields of radiofrequencies of 1800 and 2100 MHz by real-time PCR. Upon exposure of the amniocytes to electromagnetic radiation of 2100 MHz at high field strength, the expression levels of genes with important functions in the Wnt signaling pathways as well as neurogenesis-related genes were increased. The findings suggest that radiofrequency at high field strengths can have genotoxic effects during pregnancy. [ABSTRACT FROM AUTHOR]

The underlying mechanisms that determine gene expression and chromatin accessibility in retinogenesis are poorly understood. Herein, single‐cell RNA sequencing and single‐cell assay for transposase‐accessible chromatin sequencing are performed on human embryonic eye samples obtained 9–26 weeks after conception to explore the heterogeneity of retinal progenitor cells (RPCs) and neurogenic RPCs. The differentiation trajectory from RPCs to 7 major types of retinal cells are verified. Subsequently, diverse lineage‐determining transcription factors are identified and their gene regulatory networks are refined at the transcriptomic and epigenomic levels. Treatment of retinospheres, with the inhibitor of RE1 silencing transcription factor, X5050, induces more neurogenesis with the regular arrangement, and a decrease in Müller glial cells. The signatures of major retinal cells and their correlation with pathogenic genes associated with multiple ocular diseases, including uveitis and age‐related macular degeneration are also described. A framework for the integrated exploration of single‐cell developmental dynamics of the human primary retina is provided. [ABSTRACT FROM AUTHOR]

Most adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co‐activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs, supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild‐type Yap1 in adult NSCs did not induce NSC activation, suggesting tight upstream control mechanisms, but overexpression of a gain‐of‐function mutant (Yap1‐5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed a partial induction of an activated NSC gene expression program. Furthermore, Yap1‐5SA expression also induced expression of Taz and other key components of the Yap/Taz regulon that were previously identified in glioblastoma stem cell‐like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, aberrant cell differentiation, and partial acquisition of a glioblastoma stem cell‐like signature. Synopsis: In the adult hippocampus, most neural stem cells are quiescent and only few become activated and generate new neurons. This study demonstrates an important role of the transcriptional activator Yap1 in mediating the transition between quiescence and activation. Yap1 activity is enriched in activated neural stem cells.Loss‐of‐function and gain‐of‐function experiments support that Yap1 promotes neural stem cell activation.Prolonged Yap1 gain‐of‐function represses hippocampal neurogenesis.Prolonged Yap1 activation leads to aberrant neural cell differentiation and partial glioblastoma stem cell‐like signature. [ABSTRACT FROM AUTHOR]

Sex-specific differences in behavior have been observed in anxiety and learning in children exposed to prenatal inflammation; however, whether these behaviors manifest differently by age is unknown. This study assesses possible behavioral changes due to in utero inflammation as a function of age in neonatal, juvenile, and adult animals and presents potential molecular targets for observed differences. CD-1 timed pregnant dams were injected in utero with lipopolysaccharide (LPS, 50 μg/animal) or saline at embryonic day 15. No differences in stress responses were measured by neonatal ultrasonic vocalizations between LPS- and saline-exposed groups of either sex. By contrast, prenatal inflammation caused a male-specific increase in anxiety in mature but not juvenile animals. Juvenile LPS-exposed females had decreased movement in open field testing that was not present in adult animals. We additionally observed improved memory retrieval after in utero LPS in the juvenile animals of both sexes, which in males may be related to a perseverative phenotype. However, there was an impairment of long-term memory in only adult LPS-exposed females. Finally, gene expression analyses revealed that LPS induced sex-specific changes in genes involved in hippocampal neurogenesis. In conclusion, intrauterine inflammation has age- and sex-specific effects on anxiety and learning that may correlate to sex-specific disruption of gene expression associated with neurogenesis in the hippocampus. [ABSTRACT FROM AUTHOR]

Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages. Results: Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling. Conclusions: The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis. [ABSTRACT FROM AUTHOR]

Abstract Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low self‑esteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors. This article integrates affective neuroscience, psychopharmacology, neuroanatomy and molecular biology data. In addition, there are two problems with current MDD treatments, namely: 1) Low rates of responsiveness to antidepressants and too slow onset of therapeutic effect; 2) Increased stress vulnerability and autonomy, which reduces the responses of currently available treatments. In the present review, we encourage the prospection of new bioactive agents for the development of treatments with post-transduction mechanisms, neurogenesis and pharmacogenetics inducers that bring greater benefits, with reduced risks and maximized access to patients, stimulating the field of research on mood disorders in order to use the potential of preclinical studies. For this purpose, improved animal models that incorporate the molecular and anatomical tools currently available can be applied. Besides, we encourage the study of drugs that do not present "classical application" as antidepressants, (e.g., the dissociative anesthetic ketamine and dextromethorphan) and drugs that have dual action mechanisms since they represent potential targets for novel drug development more useful for the treatment of MDD. [ABSTRACT FROM AUTHOR]

During metamorphosis of solitary ascidians, part of the larval tubular nervous system is recruited to form the adult central nervous system (CNS) through neural stem-like cells called ependymal cells. The anteroposterior (AP) gene expression patterning of the larval CNS regionalize the distribution of the ependymal cells, which contains the positional information of the neurons of the adult nervous system. In colonial ascidians, the CNS of asexually developed zooids has the same morphology of the one of the post-metamorphic zooids. However, its development follows a completely different organogenesis that lacks embryogenesis, a larval phase and metamorphosis. In order to describe neurogenesis during asexual development (blastogenesis), we followed the expression of six CNS AP patterning genes conserved in chordates and five neural-related genes to determine neural cell identity in Botryllus schlosseri. We observed that a neurogenesis occurs de novo on each blastogenic cycle starting from a neurogenic transitory structure, the dorsal tube. The dorsal tube partially co-opts the AP patterning of the larval CNS markers, and potentially combine the neurogenesis role and provider of positional clues for neuron patterning. This study shows how a larval developmental module is reused in a direct asexual development in order to generate the same structures. • Nervous system develops de novo during Botryllus schlosseri blastogenetic cycle. • Asexual neurogenesis origins from a transitory tubular structure, the dorsal tube. • Dorsal tube formation and neurulation share similar anteroposterior patterning. [ABSTRACT FROM AUTHOR]

Abstract Inflammation is a defensive response of the body and is at the center of many diseases' process like depression. High mobility group protein box 1 (HMGB1), has been proved to function as a pro-inflammatory cytokine. We aim to explore the role of HMGB1 played in the neuroinflammation here. In this study, we used LPS to induce an acute inflammatory response, and to measure the anti-neuroinflammation effect of icariin (ICA) and icaritin (ICT). We found that LPS could increase the expression of HMGB1 in serum and hippocampus, along with a high expression of HMGB1 in the cytoplasm and a high expression of RAGE, which could be rescued by ICA and ICT, and ethyl pyruvate (EP) pretreatment showed similar effects here. We speculated that the translocation of HMGB1 from the nucleus to the cytoplasm played an important role in neuroinflammatory process, and HMGB1-RAGE signal was involved in this process. Furthermore, we found that ICA and ICT treatment activated TLR4-XBP1s related NF-κB signal, which we thought was relevant with the neuroprotective effect of ICA and ICT. However, EP pretreatment suppressed TLR4-XBP1s- endoplasmic reticulum stress related NF-κB signal to anti-inflammatory response, which was almost absolutely opposite with ICA and ICT treatment. We speculated that it might be caused by the duration of inflammation. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and might show a neuroprotective effect via activating TLR4-XBP1s related NF-κB signal at the same time, making it possible to act as an anti-neuroinflammatory drugs. Highlights • HMGB1-RAGE signaling and TLR4-XBP1s-NF-κB signaling were involved in neuroinflammation. • Icariin and icaritin could ameliorate neuroinflammation via suppressing HMGB1-RAGE signaling. • Icariin and icaritin might promote neuroregeneration via activating TLR4-NF-κB signaling. [ABSTRACT FROM AUTHOR]

Alterations in adult neurogenesis have been regarded as a major cause of cognitive impairment in Alzheimer’s disease (AD). The underlying mechanism of neurogenesis deficiency in AD remains unclear. In this study, we reported that Integrin-linked Kinase (ILK) protein levels and phosphorylation were significantly decreased in the hippocampus of APP/PS1 mice. Increased ILK expression of dentate gyrus (DG) rescued the hippocampus-dependent neurogenesis and memory deficits in APP/PS1 mice. Moreover, we demonstrated that the effect of ILK overexpression in the hippocampus was exerted via AKT-GSK3β pathway. Finally, we found that Fluoxetine, a selective serotonin reuptake inhibitor, could improve the impaired hippocampal neurogenesis and memory by enhancing ILK-AKT-GSK3β pathway activity in APP/PS1 mice. Thus, these findings demonstrated the effects of ILK on neurogenesis and memory recovery, suggesting that ILK is an important therapeutic target for AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine. [ABSTRACT FROM AUTHOR]

The cerebral cortex contains an enormous number of neurons, allowing it to perform highly complex neural tasks. Understanding how these neurons develop at the correct time and place and in accurate numbers constitutes amajor challenge. Here, we demonstrate a novel role for Gli3, a key regulator of cortical development, in cortical neurogenesis. We show that the onset of neuron formation is delayed in Gli3 conditional mouse mutants. Gene expression profiling and cell cycle measurements indicate that shortening of the G1 and S phases in radial glial cells precedes this delay. Reduced G1 length correlates with an upregulation of the cyclin-dependent kinase gene Cdk6, which is directly regulated by Gli3. Moreover, pharmacological interference with Cdk6 function rescues the delayed neurogenesis in Gli3 mutant embryos. Overall, our data indicate that Gli3 controls the onset of cortical neurogenesis by determining the levels of Cdk6 expression, thereby regulating neuronal output and cortical size. [ABSTRACT FROM AUTHOR]

In the developing central nervous system, transcription factors play a crucial role in the regulation of cell fate. Previously we demonstrated that LHX2 is a critical regulator of the neuron-glia cell fate switch in the developing mouse hippocampus. Here, we test LHX2 target gene Pax6 for a role in this process. We report that Pax6 overexpression is able to suppress the enhanced astrogliogenesis arising due to loss of functional LHX2. Furthermore, we show that like Lhx2, Pax6 is also able to suppress induced astrogliogenesis caused by overexpression of progliogenic factor Nfia. This demonstrates that overexpression of Pax6 can substitute for Lhx2 in the regulation of the neuronal versus glial cell fate in the developing hippocampus, and therefore, supports a role for PAX6 as a mediator of LHX2 function in this process. [ABSTRACT FROM AUTHOR]

Transcription factor Runx1 (Runt Related Transcription Factor 1), plays an important role in the differentiation of hematopoetic stem cells, angiogenesis and the development of nociceptive neurons. These known functions have in common that they relate to lineage decisions. We thus asked whether such role might also be found for Runx1 in adult hippocampal neurogenesis as a process, in which such decisions have to be regulated lifelong. Runx1 shows a widespread low expression in the adult mouse brain, not particularly prominent in the hippocampus and the resident neural precursor cells. Isoforms 1 and 2 of Runx1 (but not 3 to 5) driven by the proximal promoter were expressed in hippocampal precursor cells ex vivo, albeit again at very low levels, and were markedly increased after stimulation with TGF-β1. Under differentiation conditions (withdrawal of growth factors) Runx1 became down-regulated. Overexpression of Runx1 in vitro reduced proliferation, increased survival of precursor cells by reducing apoptosis, and increased neuronal differentiation, while slightly reducing dendritic morphology and complexity. Transfection with dominant-negative Runx1 in hippocampal precursor cells in vitro did not result in differences in neurogenesis. Hippocampal expression of Runx1 correlated with adult neurogenesis (precursor cell proliferation) across BXD recombinant strains of mice and covarying transcripts enriched in the GO categories “neural precursor cell proliferation” and “neuron differentiation”. Runx1 is thus a plausible candidate gene to be involved in regulating initial differentiation-related steps of adult neurogenesis. It seems, however, that the relative contribution of Runx1 to such effect is complementary and will explain only small parts of the cell-autonomous pro-differentiation effect. [ABSTRACT FROM AUTHOR]

During development, generation of neurons is coordinated by the sequential activation of gene expression programs by stage- and subtype-specific transcription factor networks. The SoxC group transcription factors, Sox4 and Sox11, have recently emerged as critical components of this network. Initially identified as survival and differentiation factors for neural precursors, SoxC factors have now been linked to a broader array of developmental processes including neuronal subtype specification, migration, dendritogenesis and establishment of neuronal projections, and are now being employed in experimental strategies for neuronal replacement and axonal regeneration in the diseased central nervous system. This review summarizes the current knowledge regarding SoxC factor function in CNS development and disease and their promise for regeneration. [ABSTRACT FROM AUTHOR]

Adult hippocampal neurogenesis occurs throughout life and supports healthy brain functions. The production of new neurons decreases with age, and deficiencies in adult neurogenesis are associated with neurodevelopmental and degenerative disease. The rate of neurogenesis is dynamically sensitive to an individual's environmental conditions and experiences, and certain stimuli are known robustly to enhance neurogenesis in rodent models, including voluntary exercise, enriched environment, and electroconvulsive shock. In these models, information about an organism's environment and physiological state are relayed to neurogenic cell types within the hippocampus through a series of tissue and cellular interfaces, ultimately eliciting a neurogenic response from neural stem cells and newborn neurons. Therefore, an understanding of the way that novel genes and proteins act in specific cell types within this circuit-level context is of scientific and therapeutic value. Several well-studied neurotrophic factors have been implicated in environmentally enhanced neurogenesis. This review highlights recently discovered, novel molecular mediators of neurogenesis in response to environmental cues and summarizes the contribution of advanced, large-scale gene expression and function assessment technology to past, present, and future efforts aimed at elucidating cell-type-specific molecular mediators of environmentally enhanced neurogenesis. [ABSTRACT FROM AUTHOR]

Despite a robust capacity for adult neurogenesis in the olfactory epithelium (OE), olfactory sensory losses are common. Identification of mechanisms regulating adult OE neurogenesis is, therefore, of interest. MicroRNAs (miRNAs) are broadly important in regulating vertebrate neurodevelopment, and are required in embryonic olfactory differentiation. We report here that a panel of miRNAs is differentially expressed by either progenitor or progeny cells in the regenerating mouse OE. Progenitor cells were purified from lesioned OE based on c-Kit expression, and miRNA expression was assayed in c-Kit (+) and c-Kit (-) cell populations. 28 miRNAs were significantly downregulated by at least 4 fold in the c-Kit (+) fraction, which marks the globose basal progenitor cell population. In addition, 10 miRNAs were upregulated in these basal cells. MiR-486, the most strongly downregulated miRNA identified, was further characterized to verify results. MiR-486 expression was confirmed in the c-Kit (-) OE layers using in situ hybridization. As a functional assay, over-expression of miR-486 in purified c-Kit (+) basal cell cultures resulted in a reduction in neurogenesis, consistent with a possible negative feedback regulatory model. Our data provide new insights regarding miRNA expression and function during adult OE neurogenesis, and identify candidate miRNAs warranting further study. [ABSTRACT FROM AUTHOR]

Neurogenesis, the process by which neurons are generated in the brain from progenitor cells, occurs in the subventricular zone (SVZ) and the subgranular zone (SGZ) in the adult human brain. Recently, rodent studies have demonstrated that exercise can increase neurogenesis in the SGZ; however, it is unclear if exercise also has this effect in more complex mammalian brains. The overarching aim of this study was to explore whether exercised-induced neurogenesis occurs in larger mammalian brains more representative of human brains and to explore the use of a model for exercising large animals such as sheep. For these studies, 6 male twin lambs had a structured exercise regime for 4 wk and 6 other twin male lambs were kept in an open field pen. All lambs were injected with bromodeoxyuridine (BrdU), a thymidine analog that is incorporated into the DNA of proliferating cells. Immunoperoxidase was used to visualize and quantify BrdU-positive cells in the SVZ and SGZ. Overall, no significant change in the number or distribution of BrdU-positive cells was observed in the lamb SVZ and SGZ with exercise or colabeling of BrdU with mature neuronal or glial markers in the exercised and nonexercised lamb SVZ and SGZ. Overall, this study provides a novel methodology to investigate the effects of imposed exercise on large animals and exerciseinduced neurogenesis in animals with gyrencephalic brains. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNA) are small non-coding molecules that revolutionized our knowledge about the regulation of gene expression. Capable to target a large number of mRNA, miRNA are thought to regulate around 30% of the entire human genome. Therefore, these molecules are able to regulate several biological processes, including neuronal survival, differentiation and regeneration. Additionally, miRNA might act as valuable clinical agents in brain pathological conditions. Their specific expression patterns in the brain parenchyma and/or in circulating fluids have been highlighted as potential biomarkers, while the modulation of their activity may have therapeutic value for several neurodegenerative diseases. In this review, we describe miRNA biogenesis, signaling and regulation as well as the role of miR-9, miR-124, miR-132 and miR-137 in both adult neurogenesis and neurodegeneration, namely in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The relationship between miRNA, neurodegeneration and neurogenesis will be highlighted. Moreover, the benefits, outcomes and limitations of therapies using miRNA technology for neurodegenerative disorders will also be discussed. [ABSTRACT FROM AUTHOR]

The ventral mesencephalic neural precursor cells (vmNPCs) that give rise to dopaminergic (DA) neurons have been identified by the expression of distinct genes (e.g., Lmx1a , Foxa2 , Msx1/2 ). However, the commitment of these NPCs to the mesencephalic DA neuronal fate has not been functionally determined. Evaluation of the plasticity of vmNPCs suggests that their commitment occurs after E10.5. Here we show that E9.5 vmNPCs implanted in an ectopic area of E10.5 mesencephalic explants, retained their specification marker Lmx1a and efficiently differentiated into neurons but did not express the gene encoding tyrosine hydroxylase (Th), the limiting enzyme for dopamine synthesis. A proportion of E10.5-E11.5 implanted vmNPCs behaved as committed, deriving into Th + neurons in ectopic sites. Interestingly, implanted cells from E12.5 embryos were unable to give rise to a significant number of Th + neurons. Concomitantly, differentiation assays in culture and in mesencephalic explants treated with Fgf2+LIF detected vmNPCs with astrogenic potential since E11.5. Despite this, a full suspension of E12.5 vmNPCs give rise to DA neurons in a similar proportion as those of E10.5 when they were transplanted into adult brain, but astrocytes were only detected with the former population. These data suggest that the subventricular postmitotic progenitors present in E12.5 ventral mesencephalon are unable to implant in embryonic explants and are the source of DA neurons in the transplanted adult brain. Based on our findings we propose that during DA differentiation committed vmNPCs emerge at E10.5 and they exhaust their neurogenic capacity with the rise of NPCs with astrogenic potential. [ABSTRACT FROM AUTHOR]

The presence of the neuronal-specific Nl-Src splice variant of the C-Src tyrosine kinase is conserved through vertebrate evolution, suggesting an important role in complex nervous systems. Alternative splicing involving an Nl-Src-specific microexon leads to a 5 or 6 aa insertion into the SH3 domain of Src. A prevailing model suggests that N1-Src regulates neuronal differentiation via cytoskeletal dynamics in the growth cone. Here we investigated the role of nl-src in the early development of the amphibian Xenopus tropicalis, and found that nl-src expression is regulated in entbryogenesis, with highest levels detected during the phases of primary and secondary neurogenesis. In situ hybridization analysis, using locked nucleic acid oligo probes complementary to the nl-src microexon, indicates that nl-src expression is highly enriched in the open neural plate during neurula stages and in the neural tissue of adult frogs. Given the nl-src expression pattern, we investigated a possible role for nl-src in neurogenesis. Using splice site-specific antisense morpholino oligos, we inhibited nl-src splicing, while preserving c-src expression. Differentiation of neurons in the primary nervous system is reduced in n 1-str-knockdown embryos, accompanied by a severely impaired touch response in later development. These data reveal an essential role for nl-src in amphibian neural development and suggest that alternative splicing of C-Src in the developing vertebrate nervous system evolved to regulate neurogenesis. [ABSTRACT FROM AUTHOR]

Sox3 is a single-exon gene located on the X chromosome in most vertebrates. It belongs to the SoxB1 subfamily, which is part of the larger Sox family. Previous studies have revealed that Sox3 is expressed in many fish species. However, how Sox3 influences the development of Misgurnus anguillicaudatus remains unknown. In this study, a Sox3 homologue, termed MaSox3, was cloned from the brain of M. anguillicaudatus using homology-based cloning and the rapid amplification of cDNA ends method. Sequence analysis reveals that MaSox3 encodes a hydrophilic protein, which contains a characteristic HMG-box DNA-binding domain of 79 amino acids, and shares high homology with Sox3 in other species. Additionally, quantitative real-time reverse transcription PCR and in situ hybridization showed that MaSox3 is consistently expressed during embryogenesis, with peak expression during the neurula stage and broad expression in the central nervous system. Moreover, tissue distribution analyses have revealed that MaSox3 is abundant in the adult brain, the particle cell layer, and the gonad. Additionally, its expression is observed in primary spermatocyte cells, primary oocytes and previtellogenic oocyte cells. Taken together, all of these results suggest that the expression of the MaSox3 gene is highly conserved during vertebrate evolution and involved in a wide range of developmental processes including embryogenesis, neurogenesis and gonad development. [ABSTRACT FROM AUTHOR]

The role of glutamate in the regulation of neurogenesis is well-established, but the role of vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters (EAATs) in controlling adult neurogenesis is unknown. Here we investigated the implication of VGLUTs in the differentiation of subventricular zone (SVZ)-derived neural precursor cells (NPCs). Our results show that NPCs express VGLUT1-3 and EAAT1-3 both at the mRNA and protein level. Their expression increases during differentiation closely associated with the expression of marker genes. In expression analyses we show that VGLUT1 and VGLUT2 are preferentially expressed by cultured SVZ-derived doublecortin+ neuroblasts, while VGLUT3 is found on GFAP+ glial cells. In cultured NPCs, inhibition of VGLUT by Evans Blue increased the mRNA level of neuronal markers doublecortin, B3T and MAP2, elevated the number of NPCs expressing doublecortin protein and promoted the number of cells with morphological appearance of branched neurons, suggesting that VGLUT function prevents neuronal differentiation of NPCs. This survival- and differentiation-promoting effect of Evans blue was corroborated by increased AKT phosphorylation and reduced MAPK phosphorylation. Thus, under physiological conditions, VGLUT1-3 inhibition, and thus decreased glutamate exocytosis, may promote neuronal differentiation of NPCs. [ABSTRACT FROM AUTHOR]

In the adult olfactory epithelium, the transcription factors Pax6 and Sox2 are co-expressed in sustentacular cells, horizontal basal cells (HBCs), and less-differentiated globose basal cells (GBCs)–both multipotent and transit amplifying categories—but are absent from immediate neuronal precursor GBCs and olfactory sensory neurons (OSNs). We used retroviral-vector transduction to over-express Pax6 and Sox2 individually and together during post-lesion recovery to determine how they regulate neuronal differentiation. Both Pax6 and Sox2, separately and together, can suppress the production of OSNs, as fewer clones contain neurons than with empty vector (EV), although this effect is not absolute. In this regard, Pax6 has the strongest effect when acting alone. In clones where neurons form, Pax6 reduces neuron numbers by comparison with EV, while Sox2 expands their numbers. Co-transduction with Pax6 and Sox2 produces an intermediate result. The increased production of OSNs driven by Sox2 is due to the expansion of neuronal progenitors, since proliferation and the numbers of Ascl1, Neurog1, and NeuroD1-expressing GBCs are increased. Conversely, Pax6 seems to accelerate neuronal differentiation, since Ascl1 labeling is reduced, while Neurog1- and NeuroD1-labeled GBCs are enriched. As a complement to the over-expression experiments, elimination of Sox2 in spared cells of floxed Sox2 mice, by retroviral Cre or by K5-driven CreERT2, reduces the production of OSNs and non-neuronal cells during OE regeneration. These data suggest that Pax6 and Sox2 have counteracting roles in regulating neurogenesis, in which Pax6 accelerates neuronal production, while Sox2 retards it and expands the pool of neuronal progenitors. [ABSTRACT FROM AUTHOR]

The biologic studies of human neural crest stem cells (hNCSCs) are extremely challenging due to the limited source of hNCSCs as well as ethical and technical issues surrounding isolation of early human embryonic tissues. On the other hand, vast majority of studies on MycN have been conducted in human tumor cells, thus, the role of MycN in normal human neural crest development is completely unknown. In the present study, we determined the role of MycN in hNCSCs isolated from in vitro-differentiating human embryonic stem cells (hESCs). For the first time, we show that suppression of MycN in hNCSCs inhibits cell growth and cell cycle progression. Knockdown of MycN in hNCSCs increases the expression of Cdkn1a, Cdkn2a and Cdkn2b, which encodes the cyclin-dependent kinases p21CIP1, p16 INK4a and p15INK4b. In addition, MycN is involved in the regulation of human sympathetic neurogenesis, as knockdown of MycN enhances the expression of key transcription factors involved in sympathetic neuron differentiation, including Phox2a, Phox2b, Mash1, Hand2 and Gata3. We propose that unlimited source of hNCSCs provides an invaluable platform for the studies of human neural crest development and diseases. [ABSTRACT FROM AUTHOR]

During somite segmentation, mRNA expression of the mouse Notch ligand Delta-like1 (Dll1) oscillates synchronously in the presomitic mesoderm (PSM). However, the dynamics of Dll1 protein expression were rather controversial, and their functional significance was not known. Recent live-imaging analysis showed that Dll1 protein expression also oscillates synchronously in the PSM. Interestingly, accelerated or delayed Dll1 expression by shortening or elongating the Dll1 gene, respectively, dampens or quenches Dll1 oscillation at intermediate levels, a phenomenon known as “amplitude/oscillation death” of coupled oscillators in mathematical modeling. Under this condition, oscillation of the Notch effector Hes7 is also dampened, leading to severe fusion of somites and their derivatives, such as vertebrae and ribs. Thus, the appropriate timing of Dll1 expression is critical for its oscillatory expression, pointing to the functional significance of Dll1-mediated oscillatory cell–cell interactions in the segmentation clock. In neural stem cells, Dll1 expression is also oscillatory, but non-synchronous, and when Dll1 oscillation is dampened, oscillation of another Notch effector, Hes1, is also dampened, leading to defects of neural development. In this review, we discuss the underlying mechanism for the different oscillatory dynamics (synchronous versus non-synchronous) in the PSM and neural stem cells in a unified manner. [ABSTRACT FROM AUTHOR]

We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain regionspecific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10mgkg-1 body weight by gavage for 28days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related tomyelination (Plp1 and Mbp) inthe hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirmChrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrusmay also detect possible developmental neurotoxic effects. [ABSTRACT FROM AUTHOR]

Metallothionein (MT) is a small cysteine-rich heavy metal-binding protein involved in metal homeostasis, detoxification and free radical-scavenging. MT is ubiquitously expressed in several tissues, but its role in the central nervous system is not well understood. In this study, we identified two MT homologous genes ( mt2 and smtb ) in the zebrafish. Digoxigenin- in situ hybridization showed the expression of mt2 and smtb genes in the ventricular layers in the telencephalon, diencephalon, mesencephalon and rhombencephalon, most of which are cell proliferating regions in the brain of zebrafish. Cellular characteristics of MT genes expressing cells were examined by double-labelling with markers for neurons (HuC/D) and astrocytes (glial fibrillary acidic protein, GFAP and S100 protein) and cell proliferation marker (PCNA). mt2 and smtb mRNAs are expressed in neurons and not in astrocytes, and they were co-localized with PCNA. These results suggest that mt2 and smtb may play an important role in neurogenesis and neuroprotection. [ABSTRACT FROM AUTHOR]

V1 interneurons are inhibitory neurons that play an essential role in vertebrate locomotion. The molecular mechanisms underlying their genesis remain, however, largely undefined. Here, we show that the transcription factor Prdm12 is selectively expressed in p1 progenitors of the hindbrain and spinal cord in the frog embryo, and that a similar restricted expression profile is observed in the nerve cord of other vertebrates as well as of the cephalochordate amphioxus. Using frog, chick and mice, we analyzed the regulation of Prdm12 and found that its expression in the caudal neural tube is dependent on retinoic acid and Pax6, and that it is restricted to p1 progenitors, due to the repressive action of Dbx1 and Nkx6-1/2 expressed in the adjacent p0 and p2 domains. Functional studies in the frog, including genomewide identification of its targets by RNA-seq and ChIP-Seq, reveal that vertebrate Prdm12 proteins act as a general determinant of V1 cell fate, at least in part, by directly repressing Dbx1 and Nkx6 genes. This probably occurs by recruiting the methyltransferase G9a, an activity that is not displayed by the amphioxus Prdm12 protein. Together, these findings indicate that Prdm12 promotes V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes, and suggest that this function might have only been acquired after the split of the vertebrate and cephalochordate lineages. [ABSTRACT FROM AUTHOR]

Notch signalling, SoxB and Group A bHLH 'proneural' genes are conserved regulators of the neurogenic program in many bilaterians. However, the ancestry of their functions and interactions is not well understood. We address this question in the sea anemone Nematostella vectensis, a representative of the Cnidaria, the sister clade to the Bilateria. It has previously been found that the SoxB orthologue NvSoxB(2) is expressed in neural progenitor cells (NPCs) in Nematostella and promotes the development of both neurons and nematocytes, whereas Notch signalling has been implicated in the negative regulation of neurons and the positive regulation of nematocytes. Here, we clarify the role of Notch by reporting that inhibition of Notch signalling increases the numbers of both neurons and nematocytes, as well as increasing the number of NvSoxB(2)- expressing cells. This suggests that Notch restricts neurogenesis by limiting the generation of NPCs. We then characterise NvAth-like (Atonal/Neurogenin family) as a positive regulator of neurogenesis that is co-expressed with NvSoxB(2) in a subset of dividing NPCs, while we find that NvAshA (Achaete-scute family) and NvSoxB(2) are co-expressed in non-dividing cells only. Reciprocal knockdown experiments reveal a mutual requirement for NvSoxB(2) and NvAth-like in neural differentiation; however, the primary expression of each gene is independent of the other. Together, these data demonstrate that Notch signalling and NvSoxB(2) regulate Nematostella neural progenitors via parallel yet interacting mechanisms; with different aspects of these interactions being shared with Drosophila and/or vertebrate neurogenesis. [ABSTRACT FROM AUTHOR]

Efficient differentiation is important for regenerative medicine based on pluripotent stem cells, including treatment of neurodegenerative disorders and trauma. Baicalin promotes neuronal differentiation of neural stem/progenitor cells of rats and mice. To evaluate the suitability of baicalin for neuronal differentiation of human iPS cells, we investigated whether it promotes neuronal differentiation in human iPS cells and monitored basic helix-loop-helix (bHLH) gene expression during neuronal differentiation. Baicalin promoted neuronal differentiation and inhibited glial differentiation, suggesting that baicalin can influence the neuronal fate decision in human iPS cells. Notch signaling, which is upstream of bHLH proteins, was not involved in baicalin-induced neuronal differentiation. Baicalin treatment did not down-regulate Hes1 gene expression, but it reduced Hes1 protein levels and up-regulated Ascl1 gene expression. Thus, baicalin promoted neuronal differentiation via modulation of bHLH transcriptional factors. Therefore, baicalin has potential to be used as a small-molecule drug for regenerative treatment of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The nuclear receptor steroidogenic factor-1 (SF-1) plays essential roles in the development and function of the endocrine and reproductive systems. During embryogenesis, SF-1 is expressed in the ventromedial hypothalamic nucleus (VMH) and regulates the migration and terminal differentiation of the VMH neurons. Additionally, in situ hybridization data indicated SF-1 expression in the dorsal telencephalon at embryonic day (E) 13.5. In this study, we investigated the neocortical development in SF-1 knockout (KO) mouse embryos. The number of neurons was increased in the intermediate/subventricular zones and decreased in the cortical plate in the SF-1 KO embryos. SF-1 KO embryos produced more neural stem/progenitor cells, especially apical progenitor cells, and showed abnormal radial glial fiber morphology. The increase in neural stem/progenitor cells was caused by an increased S-phase fraction in the proliferative cells and the inhibition of cell cycle exit in these cells. The mRNA expression of the estrogen receptor ESRα was up-regulated and that of the estrogen synthetase Cyp19a1 was down-regulated in the dorsal telencephalon of SF-1 KO embryos. We showed that SF-1 is expressed in the dorsal telencephalon at E15.5 and E18.5, but not in adult animals. Our data demonstrated that SF-1 is involved in cell cycle regulation, neurogenesis, and neuronal migration via controlling the estrogen signaling for proper neocortical development. [ABSTRACT FROM AUTHOR]

Sensory neurons in the head are largely generated from neurogenic placodes. Previous studies have revealed early events in placode development; however, the process of maturation has not been studied. In this study, it has been shown that placodal neurogenesis follows a sequential progression with distinct stages defined by expression of specific markers. These markers highlight domains of maturation within the stream of migratory neuroblasts that extend between the placode and the neural tube. Commitment to neurogenesis occurs in the apical placode, with the newborn neuroblasts delaminating basally and entering a transition zone. The neuroblasts migrate through the transition zone, differentiating further and becoming post-mitotic as they approach the ganglionic anlage. It has further been demonstrated that this progression from the transition zone to the ganglionic anlage is accompanied by a switch from multipolar to bipolar cell morphology. This sequential progression parallels events observed elsewhere in the nervous system, but here the stages are distinct and anatomically segregated. It is proposed that placodal neurogenesis provides a tractable system to examine the transition between states in neurogenesis. [ABSTRACT FROM AUTHOR]

Doublecortin (DCX) is a microtubule-associated protein that has been considered a marker for neuronal precursors and young migrating neurons during the development of the central nervous system and in adult neurogenic niches. The retina of fishes represents an accessible, continuously growing and highly structured (layered) part of the central nervous system and, therefore, offers an exceptional model to extend our knowledge on the possible role of DCX in promoting neurogenesis and migration to appropriate layers. We have analyzed the distribution of DCX in the embryonic and postembryonic retina of a small shark, the lesser spotted dogfish Scyliorhinus canicula , by means of immunohistochemistry. We investigated the relationship between DCX expression and the neurogenic state of DCX-labeled cells by exploring its co-localization with the proliferation marker PCNA (proliferating cell nuclear antigen) and the marker of neuronal differentiation HuC/D. Since radially migrating neurons use radial glial fibers as substrate, we explored the possible correlation between DCX expression and cell migration along radial glia by comparing its expression with that of the glial marker GFAP (glial fibrillary acidic protein). Additionally, we characterized DCX-expressing cells by double immunocytochemistry using antibodies against Calbindin (a marker for mature bipolar and horizontal cells in this species) and Pax6, which has been proposed as a regulator of cell proliferation, cell differentiation, and neuron diversification in the neural retina of sharks. Strong DCX immunoreactivity was observed in immature cells and cell processes, at a time when retinal cells were not yet organized into different laminae. DCX was also found in subsets of mature ganglion, amacrine, bipolar and horizontal cells long after they had exited the cell cycle, a pattern that was maintained in juveniles and adults. Our results on DCX expression in the retina are compatible with a role for DCX in cell migration within the immature retina, and in dynamic neuronal plasticity in the mature retina. We also provide evidence of DCX expression in discrete cells in the retinal pigment epithelium of prehatching embryos and juveniles, which suggest that retinal pigmented epithelial cells in sharks, as in mammals, have an intrinsic capacity to proliferate and differentiate into cells with neural identity. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n = 8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p = 0.014), hsa-miR-212-3p: mean decrease of 76.9% (p = 0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3′-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3′-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3′-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export. [ABSTRACT FROM AUTHOR]

Mesial temporal lobe epilepsy ( MTLE) is characterized by spontaneous recurrent complex partial seizures. Increased neurogenesis and neuronal plasticity have been reported in animal models of MTLE, but not in detail in human MTLE cases. Here, we showed that receptor for activated C kinase 1 ( RACK1) was expressed in the hippocampus and temporal cortex of the MTLE human brain. Interestingly, most of the cells expressing RACK1 in the epileptic temporal cortices co-expressed both polysialylated neural cell adhesion molecules, the migrating neuroblast marker, and the beta-tubulin isotype III, an early neuronal marker, suggesting that these cells may be post-mitotic neurons in the early phase of neuronal development. A subpopulation of RACK1-positive cells also co-express neuronal nuclei, a mature neuronal marker, suggesting that epilepsy may promote the generation of new neurons. Moreover, in the epileptic temporal cortices, the co-expression of both axonal and dendritic markers in the majority of RACK1-positive cells hints at enhanced neuronal plasticity. The expression of β-tubulin II ( TUBB2B) associated with neuronal migration and positioning, was decreased. This study is the first to successfully identify a single population of cells expressing RACK1 in the human temporal cortex and the brain of the animal model, which can be up-regulated in epilepsy. Therefore, it is possible that these cells are functionally relevant to the pathophysiology of epilepsy. [ABSTRACT FROM AUTHOR]

The human subependymal zone (SEZ) is debatably a source of newly born neurons throughout life and neurogenesis is a multi-step process requiring distinct transcripts during cell proliferation and early neuronal maturation, along with orchestrated changes in gene expression during cell state/fate transitions. Furthermore, it is becoming increasingly clear that the majority of our genome that results in production of non-protein-coding RNAs plays vital roles in the evolution, development, adaptation, and region-specific function of the human brain.We predicted that some transcripts expressed in the SEZ may be unique to this specialized brain region, and that a comprehensive transcriptomic analysis of this region would aid in defining expression changes during neuronal birth and growth in adult humans. Here, we used deep RNA sequencing of human SEZ tissue during adulthood and aging to characterize the transcriptional landscape with a particular emphasis on long noncoding RNAs (lncRNAs).The data show predicted age-related changes in mRNAs encoding proliferation, progenitor, and inflammatory proteins as well as a unique subset of lncRNAs that are highly expressed in the human SEZ, many of which have unknown functions. Our results suggest the existence of robust proliferative and neuronal differentiation potential in the adult human SEZ and lay the foundation for understanding the involvement of lncRNAs in postnatal neurogenesis and potentially associated neurodevelopmental diseases that emerge after birth. [ABSTRACT FROM AUTHOR]

Since their discovery in the early 1990s, microRNAs have emerged as key components of the post-transcriptional regulation of gene expression. MicroRNAs occur in the plant and animal kingdoms, with the numbers of microRNAs encoded in the genome increasing together with the evolutionary expansion of the phyla. By base-pairing with complementary sequences usually located within the 3′ untranslated region, microRNAs target mRNAs for degradation, destabilization and/or translational inhibition. Because one microRNA can have many, if not hundreds, of target mRNAs and because one mRNA can, in turn, be targeted by many microRNAs, these small single-stranded RNAs can exert extensive pleiotropic functions during the development, adulthood and ageing of an organism. Specific functions of an increasing number of microRNAs have been described for the invertebrate and vertebrate nervous systems. Among these, the miR- 8/ miR- 200 microRNA family has recently emerged as an important regulator of neurogenesis and gliogenesis and of adult neural homeostasis in the central nervous system of fruit flies, zebrafish and rodents. This highly conserved microRNA family consists of a single ortholog in the fruit fly ( miR- 8) and five members in vertebrates ( miR- 200a, miR- 200b, miR- 200c, miR- 141 and miR- 429). Here, we review our current knowledge about the functions of the miR- 8/ miR- 200 microRNA family during invertebrate and vertebrate neural development and adult homeostasis and, in particular, about their role in the regulation of neural stem/progenitor cell proliferation, cell cycle exit, transition to a neural precursor/neuroblast state, neuronal differentiation and cell survival and during glial cell growth and differentiation into mature oligodendrocytes. [ABSTRACT FROM AUTHOR]

The brains of teleost fish show extensive adult neurogenesis and neuronal regeneration. The patterns of gene regulation during fish brain aging are unknown. The short-lived teleost fish Nothobranchius furzeri shows markers of brain aging including reduced learning performances, gliosis, and reduced adult neurogenesis. We used RNA-seq to quantify genome-wide transcript regulation and sampled five different time points to characterize whole-genome transcript regulation during brain aging of N. furzeri. Comparison with human datasets revealed conserved up-regulation of ribosome, lysosome, and complement activation and conserved down-regulation of synapse, mitochondrion, proteasome, and spliceosome. Down-regulated genes differ in their temporal profiles: neurogenesis and extracellular matrix genes showed rapid decay, synaptic and axonal genes a progressive decay. A substantial proportion of differentially expressed genes (~40%) showed inversion of their temporal profiles in the last time point: spliceosome and proteasome showed initial down-regulation and stress-response genes initial up-regulation. Extensive regulation was detected for chromatin remodelers of the DNMT and CBX families as well as members of the polycomb complex and was mirrored by an up-regulation of the H3K27me3 epigenetic mark. Network analysis showed extensive coregulation of cell cycle/ DNA synthesis genes with the uncharacterized zinc-finger protein ZNF367 as central hub. In situ hybridization showed that ZNF367 is expressed in neuronal stem cell niches of both embryonic zebrafish and adult N. furzeri. Other genes down-regulated with age, not previously associated with adult neurogenesis and with similar patterns of expression are AGR2, DNMT3A, KRCP, MEX3A, SCML4, and CBX1. CBX7, on the other hand, was up-regulated with age. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinosis (NCL) diseases consist of a group of genetically inherited neurodegenerative disorders that share common symptoms such as seizures, psychomotor retardation, blindness, and premature death. Although gene defects behind the NCL diseases are well characterized, very little is known how these defects affect normal development of the brain and cause the pathology of the disease. To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. The relationship between the expression pattern and the developmental stage of the brain showed that these genes are co-expressed spatially and temporally during brain development. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, hippocampus and cerebellum, all representing regions that are known to be associated with the formation of new neurons. More specifically, RT-PCR studies on developing mouse cortices revealed that the CLN genes were temporally co-expressed in the neural progenitor cells together with known stem cell markers. This suggested that CLN2, CLN3 and CLN5 genes may play an important role in early embryonal neurogenesis. [ABSTRACT FROM AUTHOR]

The Drosophila optic lobe is composed of a wide variety of neurons that form laminar structures and columnar units. The fly optic lobe shares structural features with the mammalian brain, and fly genetics allow precise genetic manipulations. Thus, the Drosophila visual center is an excellent model for studying the mechanisms underlying the establishment of a functional neuronal circuit during brain development. However, little is understood about the developmental mechanisms that produce neuronal diversity and establish neuronal circuits in the medulla, the largest component of the optic lobe. Our recent research revealed key features of medulla development, such as birth-order-dependent specification of neuronal types and the subdivision of the medulla primordium into concentric zones, which is characterized by the expression of four transcription factors. Here, we review recent investigations into the development of the medulla and discuss the mechanisms that establish functional neuronal circuits. [ABSTRACT FROM AUTHOR]

Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure can lead to long-lasting changes in functional and genetic programs of the brain, which may underlie behavioral alterations seen in Fetal Alcohol Spectrum Disorder (FASD). Aberrant fetal programming during gestational alcohol exposure is a possible mechanism by which alcohol imparts teratogenic effects on the brain; however, current methods used to investigate the effects of alcohol on development often rely on either direct application of alcohol in vitro or acute high doses in vivo. In this study, we used our established moderate prenatal alcohol exposure (PAE) model, resulting in maternal blood alcohol content of approximately 20 mM, and subsequent ex vivo cell culture to assess expression of genes related to neurogenesis. Proliferating and differentiating neural progenitor cell culture conditions were established from telencephalic tissue derived from embryonic day (E) 15e17 tissue exposed to alcohol via maternal drinking throughout pregnancy. Gene expression analysis on mRNA derived in vitro was performed using a microarray, and quantitative PCR was conducted for genes to validate the microarray. Student's t tests were performed for statistical comparison of each exposure under each culture condition using a 95% confidence interval. Eleven percent of genes on the array had significantly altered mRNA expression in the prenatal alcohol-exposed neural progenitor culture under proliferating conditions. These include reduced expression of Adora2a, Cxcl1, Dlg4, Hes1, Nptx1, and Vegfa and increased expression of Fgf13, Ndn, and Sox3; bioinformatics analysis indicated that these genes are involved in cell growth and proliferation. Decreased levels of Dnmt1 and Dnmt3a were also found under proliferating conditions. Under differentiating conditions, 7.3% of genes had decreased mRNA expression; these include Cdk5rap3, Gdnf, Hey2, Heyl, Pard6b, and Ptn, which are associated with survival and differentiation as indicated by bioinformatics analysis. This study is the first to use chronic low to moderate PAE, to more accurately reflect maternal alcohol consumption, and subsequent neural progenitor cell culture to demonstrate that PAE throughout gestation alters expression of genes involved in neural development and embryonic neurogenesis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Effect of indomethacin on age-related neuroinflammation and neurogenesis was investigated in 24-month-old mice. [•] Transcript expression of inflammatory mediators was upregulated in aged brains. [•] Indomethacin decreased hippocampal COX-1 and COX-2 transcript expression. [•] Gfap and Iba1 transcript expression were reduced by indomethacin in the aged hippocampus. [•] Neurogenesis was unaffected by indomethacin. [Copyright &y& Elsevier]

Highlights: [•] We examined social and gonadal control of adult neurogenesis in a eusocial rodent. [•] Dominant breeders have fewer DCX(+) cells in the DG, PCx, and BLA than subordinates. [•] DCX expression in PCx was increased by opposite-sex cues, not gonadal hormones. [•] DCX expression in BLA might be stimulated by social threat cues. [•] Results contrast work on status and neurogenesis in traditional laboratory rodents. [ABSTRACT FROM AUTHOR]