A human-specific gene-activating non-coding RNA for EFHC1, an epilepsy-associated gene, functions in the neural stem cell proliferation and cortical structure regulation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE286261 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation and survival. Disruptions lead to neurodevelopmental disorders including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1-null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.
2021-08-09 | PXD027798 |
Project description:Neural stem cells (NSCs) in the subventricular zone (SVZ) produce functional neurons throughout life and are an accessible and robust system to understand neurodevelopmental mechanisms. Elucidating the properties of NSCs will also provide insights for their use in the treatment of neurodevelopmental disorders and brain injuries. However, the epigenetic mechanisms that maintain NSCs and control neurogenesis remain unclear. We previously showed that Paupar, a CNS-expressed long non-coding RNA (lncRNA), controls neuroblastoma cell growth by binding and modulating the activity of the KAP1 transcription co-factor. We interrogated the last stages of olfactory bulb (OB) neurogenesis and showed that depletion of these two molecules in vivo reduced the number of newborn neurons and delayed their morphological differentiation. Here we investigated upstream functions of these two epigenetic regulators in SVZ NSCs self-renewal and neurogenesis. We combined studies using inducible knockout and in vivo knockdown electroporation, with molecular analysis. Our results demonstrate that KAP1 and Paupar are broadly expressed in the normal postnatal/adult SVZ neurogenic lineage, that they physically interact in SVZ cells and regulate NSC behaviour in the SVZ. KAP1 directly maintains the neural stem cell pool and regulates the expression of genes involved in the cell cycle. Paupar, in turn maintains stem cell quiescence by restricting lineage progression from stem cells to transit amplifying progenitors (TAPs). These results suggest important roles for a KAP1-Paupar containing chromatin regulatory complex in the control of SVZ NSC and SVZ-OB neurogenesis.
2025-09-24 | GSE298169 | GEO
Project description:Neural stem cells (NSCs) in the subventricular zone (SVZ) produce functional neurons throughout life and are an accessible and robust system to understand neurodevelopmental mechanisms. Elucidating the properties of NSCs will also provide insights for their use in the treatment of neurodevelopmental disorders and brain injuries. However, the epigenetic mechanisms that maintain NSCs and control neurogenesis remain unclear. We previously showed that Paupar, a CNS-expressed long non-coding RNA (lncRNA), controls neuroblastoma cell growth by binding and modulating the activity of the KAP1 transcription co-factor. We interrogated the last stages of olfactory bulb (OB) neurogenesis and showed that depletion of these two molecules in vivo reduced the number of newborn neurons and delayed their morphological differentiation. Here we investigated upstream functions of these two epigenetic regulators in SVZ NSCs self-renewal and neurogenesis. We combined studies using inducible knockout and in vivo knockdown electroporation, with molecular analysis. Our results demonstrate that KAP1 and Paupar are broadly expressed in the normal postnatal/adult SVZ neurogenic lineage, that they physically interact in SVZ cells and regulate NSC behaviour in the SVZ. KAP1 directly maintains the neural stem cell pool and regulates the expression of genes involved in the cell cycle. Paupar, in turn maintains stem cell quiescence by restricting lineage progression from stem cells to transit amplifying progenitors (TAPs). These results suggest important roles for a KAP1-Paupar containing chromatin regulatory complex in the control of SVZ NSC and SVZ-OB neurogenesis.
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Project description:While thousands of long noncoding RNAs (lncRNAs) have been identified, few lncRNAs that control neural stem cell (NSC) behavior are known. Here, we identify Pinky (Pnky) as a novel, neural-specific lncRNA that regulates neurogenesis from NSCs in the embryonic and postnatal brain. In postnatal NSCs, Pnky knockdown potentiates neuronal lineage commitment and expands the transit-amplifying cell population, increasing neuron production several-fold. Pnky is evolutionarily conserved and expressed in NSCs of the developing human brain. In the embryonic mouse cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population. Pnky interacts with splicing regulator PTBP1, and PTBP1 knockdown also enhances neurogenesis. In NSCs, Pnky and PTBP1 regulate the expression and alternative splicing of a core set of transcripts that relates to the cellular phenotype. These data thus unveil Pnky as a conserved lncRNA that interacts with a key RNA processing factor and regulates a critical stage of neurogenesis from embryonic and postnatal NSC populations.
2015-03-15 | GSE65542 | GEO
Project description:In Alzheimer’s disease (AD), reduced neural stem cell (NSC) plasticity causes reduced neurogenesis. Therefore, supplying the brain with new neurons using endogenous neurogenic reservoir – NSCs - might counteract the progression of AD. However, the mechanisms that enhance NSC plasticity are unknown. We recently generated an AD model in adult zebrafish brain where NSCs could react by enhanced plasticity and neurogenesis, and identified Interleukin-4 (IL4) as a key factor underlying this ability. Although IL4 directly regulated NSCs through its receptor IL4R, it was not clear how IL4R-negative NSCs would enhance their proliferation. Here, by performing whole tissue and single cell transcriptomics, we report that IL4 regulates IL4R-negative NSCs through modulating tryptophan metabolism by reducing the availability of Serotonin (5-HT) that suppresses NSC plasticity. 5-HT receptor htr1+ is only expressed in periventricular neurons where 5-HT balances the expression of brain-derived neurotrophic factor (bdnf), which promotes NSC proliferation through its receptor NGFRA, which is predominantly expressed in IL4R-negative NSCs. AD conditions induce IL4 that reduce 5-HT levels, and suppresses the suppressive effect on BDNF levels. Elevated levels of BDNF activate, through NGFRA, the proliferative output of the IL4R-negative NSCs. 5-HT overexpression dramatically reduces BDNF and proliferative ability of NSCs. Our results identify a novel IL4-dependent balancing mechanism on NSC proliferation by 5-HT through an intermediary regulatory cascade via HTR1, and BDNF/NGFRA signaling between periventricular neurons and NSCs. Our findings mark the heterogeneity of NSCs in response to direct or indirect regulation by IL4 – a biomarker for neurodegeneration-induced NSC plasticity.
2020-01-24 | GSE124162 | GEO
Project description:Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
2020-02-19 | GSE137852 | GEO
Project description:Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether epigenetic mechanisms can maintain NSC quiescence over long term in the adult brain is not well-understood. Here we showed that adult mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, exhibited substantially enlarged DG with increased number of dentate granule cells. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promoted their activation and neurogenesis, which was countered by inhibition of histone demethylase LSD1. Mechanistically, RNA sequencing and CUT & RUN analyses of cultured quiescent adult NSCs revealed Setd1a deletion-induced transcriptional changes and Setd1a targets, among which down-regulation of Bhlhe40 promoted quiescent NSC activation in the adult DG. Together, our study revealed a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
2024-03-31 | GSE250276 | GEO
Project description:Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether epigenetic mechanisms can maintain NSC quiescence over long term in the adult brain is not well-understood. Here we showed that adult mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, exhibited substantially enlarged DG with increased number of dentate granule cells. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promoted their activation and neurogenesis, which was countered by inhibition of histone demethylase LSD1. Mechanistically, RNA sequencing and CUT & RUN analyses of cultured quiescent adult NSCs revealed Setd1a deletion-induced transcriptional changes and Setd1a targets, among which down-regulation of Bhlhe40 promoted quiescent NSC activation in the adult DG. Together, our study revealed a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
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Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.
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2014-03-06 | GSE55621 | GEO