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Single cell RNA sequencing of aging neural progenitors reveals loss of excitatory neuron potential and a population with transcriptional immune response (scRNA-Seq)

ABSTRACT: In the adult murine brain, neural stem cells (NSCs) reside in two main niches, the dentate gyrus (DG), and the subventricular zone (SVZ). In the DG, NSCs give rise to intermediate progenitors that differentiate into excitatory neurons, while progenitors in the SVZ migrate to the olfactory bulb (OB) where they mainly differentiate into inhibitory interneurons. Neurogenesis, the production of new neurons, persists throughout life but decrease dramatically during aging, concomitantly with increased inflammation. Many cell types, including microglia, undergo dramatic transcriptional changes but few such changes have been detected in neural progenitors. Furthermore, transcriptional profiles in progenitors from different neurogenic regions have not been compared at single cell level, and little is known about how they are affected by age-related inflammation. We have generated a single cell RNA sequencing dataset enriched for intermediate progenitors, which revealed that most aged neural progenitors only acquire minor transcriptional changes. However, progenitors set to become excitatory neurons decrease faster than others. In addition, a population in the aged SVZ, not detected in the OB, acquired major transcriptional activation related to immune responses. This suggests that differences in age related neurogenic decline between regions is not due to tissue differences but rather cell type specific intrinsic transcriptional programs, and that subset of neuroblasts in the SVZ react strongly to age related inflammatory cues.

ORGANISM(S): Mus musculus

PROVIDER: GSE261458 | GEO | 2024/07/29

REPOSITORIES: GEO

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Single cell RNA sequencing of aging neural progenitors reveals loss of excitatory neuron potential and a population with transcriptional immune response (RNA-Seq)

Project description:In the adult murine brain, neural stem cells (NSCs) reside in two main niches, the dentate gyrus (DG), and the subventricular zone (SVZ). In the DG, NSCs give rise to intermediate progenitors that differentiate into excitatory neurons, while progenitors in the SVZ migrate to the olfactory bulb (OB) where they mainly differentiate into inhibitory interneurons. Neurogenesis, the production of new neurons, persists throughout life but decrease dramatically during aging, concomitantly with increased inflammation. Many cell types, including microglia, undergo dramatic transcriptional changes but few such changes have been detected in neural progenitors. Furthermore, transcriptional profiles in progenitors from different neurogenic regions have not been compared at single cell level, and little is known about how they are affected by age-related inflammation. We have generated a single cell RNA sequencing dataset enriched for intermediate progenitors, which revealed that most aged neural progenitors only acquire minor transcriptional changes. However, progenitors set to become excitatory neurons decrease faster than others. In addition, a population in the aged SVZ, not detected in the OB, acquired major transcriptional activation related to immune responses. This suggests that differences in age related neurogenic decline between regions is not due to tissue differences but rather cell type specific intrinsic transcriptional programs, and that subset of neuroblasts in the SVZ react strongly to age related inflammatory cues.

2024-07-29 | GSE261457 | GEO

Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis

Project description:Neural stem cells (NSCs) generate new neurons throughout life in two distinct areas of the mammalian brain: the subventricular zone (SVZ) lining the lateral ventricles and the hippocampal dentate gyrus (DG). How gene expression signatures differ among NSCs and immature neurons within and between these adult neurogenic regions is unknown. We isolated NSCs and their progeny using transgenic mice expressing GFP under the control of the Sox2 promoter (labeling NSCs) and transgenic mice expressing DsRed under the control of the doublecortin (Dcx) promoter (labeling immature neurons). Comparison of the transcriptomes of SOX2+ cells derived from both neurogenic areas revealed that NSCs are highly similar but that functionally significant differences in gene expression exist: IGF2, which is expressed only in SOX2+ cells in the DG but not in the SVZ, is required for proliferation of DG-derived but not SVZ-derived NSCs. Gene expression profiles strongly diverged in immature neurons, and we provide evidence that ephrinB3, which was up-regulated only in the DG but not in the SVZ during neuronal differentiation, regulates the survival of newborn granule cells. Thus, the data provided here show that stem cell populations in the adult DG and SVZ are similar but have unique properties that manifest themselves later during neural differentiation, resulting in distinct neuronal populations Hippocampi and SVZ from 6 week old DCX-DsRed and Sox2-GFP Reporter mice were dissected and cell sorted using FACS. cDNA were generated and analysed using Agilent Platform.

2011-12-31 | E-GEOD-21208 | biostudies-arrayexpress

Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis

2011-12-31 | GSE21208 | GEO

Analysis of Mll1-deficiency identifies neurogenic transcriptional modules and Brn4 as a factor for direct astrocyte-to-neuron reprogramming

Project description:BACKGROUND: Mixed lineage leukemia-1 (Mll1) epigenetically regulates gene expression patterns that specify cellular identity in both embryonic development and adult stem cell populations. In the adult mouse brain, multipotent neural stem cells (NSCs) in the subventricular zone (SVZ) generate new neurons throughout life and Mll1 is required for this postnatal neurogenesis but not for glial cell differentiation. Analysis of Mll1-dependent transcription may identify neurogenic genes useful for the direct reprogramming of astrocytes into neurons. OBJECTIVE: To identify Mll1-dependent transcriptional modules and determine whether genes in the neurogenic modules can be used to directly reprogram astrocytes into neurons. METHODS: We performed gene coexpression module analysis on microarray data from differentiating wild-type and Mll1-deleted SVZ NSCs. Key developmental regulators belonging to the neurogenic modules were overexpressed in Mll1-deleted cells and cultured cortical astrocytes, and cell phenotypes were analyzed by immunocytochemistry and electrophysiology. RESULTS: Transcriptional modules that correspond to neurogenesis were identified in wild-type NSCs. Modules related to astrocytes and oligodendrocytes were enriched in Mll1-deleted NSCs, consistent with their gliogenic potential. Overexpression of genes selected from the neurogenic modules enhanced the production of neurons from Mll1- deleted cells, and the overexpression of Brn4 (Pou3f4) in non-neurogenic cortical astroglia induced their transdifferentiation into electrophysiologically active neurons. CONCLUSIONS: Our results demonstrate that Mll1 is required for the expression of neurogenic - but not gliogenic - transcriptional modules in a multipotent NSC population and further indicate that specific Mll1-dependent genes may be useful for direct reprogramming strategies.

2016-03-06 | GSE56835 | GEO

Dual and separable roles for Ezh2 in neurogenic astroglia

Project description:The epigenetic mechanisms that enable specialized astrocytes to retain neurogenic competence throughout adult life are still poorly understood. Here we show that astrocytes that serve as neural stem cells (NSCs) in the adult mouse subventricular zone (SVZ) express the histone methyltransferase EZH2. This Polycomb repressive factor is required for neurogenesis independent of its role in SVZ NSC proliferation, as Ink4a/Arf-deficiency in Ezh2-deleted SVZ NSCs rescues cell proliferation, but neurogenesis remains defective. Olig2 is a direct target of EZH2, and repression of this bHLH transcription factor is critical for neuronal differentiation. Furthermore, Ezh2 prevents the inappropriate activation of genes that specify non-SVZ neuronal subtypes. In the human brain, SVZ cells including local astroglia also express EZH2, correlating with postnatal neurogenesis. Thus, EZH2 is an epigenetic regulator that distinguishes neurogenic SVZ astrocytes, orchestrating distinct and separable aspects of adult stem cell biology, which has important implications for regenerative medicine and oncogenesis. Examination of histone modifications (H3K27me3 and H3K4me3) in subventricular zone neural stem cells

2014-05-02 | E-GEOD-56394 | biostudies-arrayexpress

Single-Cell Transcriptomics and Fate Mapping of Ependymal Cells Reveals an Absence of Neural Stem Cell Function

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2018-05-02 | GSE100320 | GEO

Myelin-allied gene expression profile of adult neural progenitors shortly after onset of differentiation

Project description:Spontaneous neural repair from endogenous neural stem cells (NSCs) occurs in response to central nervous system (CNS) injuries or diseases to only a limited extent from endogenous NSCs niches. Uncovering the mechanisms that control neural repair and can be further manipulated to promote towards oligodendrocyte progenitors cells (OPCs) and myelinating oligodendrocytes is a major objective. Our aim was to identify myelin specific transcriptional regulators amongst large transcriptional changes shortly after differentiation of neural stem cells from the subventricular zone (SVZ) of adult mice SVZ-NSCs from adult mice were differentiated for 12 and 24 h in absence of growth factor (bFGF, EGF) and subjected for gene array as compared with undifferentiated NSCs cultured in presence of growth factors (n=5 samples per condition).

2016-06-01 | E-GEOD-76968 | biostudies-arrayexpress

Post-transcriptional control of a stemness signature by RNA-binding 8 protein MEX3A regulates adult neurogenesis

Project description:Neural stem cells (NSCs) in the adult mammalian subependymal zone maintain a glial identity and the developmental potential to generate neurons during the lifetime. Production of neurons from these NSCs is not direct but follows an orderly pattern of cell progression which allows the gradual increase along the neurogenic lineage in the expression of pro-neural factors needed for neuronal specification. In this context, tightly regulated translation of existing transcriptional programs represents a potential mechanism to avoid the critical challenge posed by genes that encode proteins with conflicting functions, i.e. self-renew or differentiate. Here, we identify RNA-binding protein MEX3A as a post-transcriptional regulator of a set of stemness-associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A binding to a set of quiescence-related RNAs in activated NSCs is needed for their return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A is a pivotal regulator of adult mammalian neurogenesis acting as a translational remodeller.

2023-01-08 | PXD038983 | Pride

Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson's disease

Project description:It is currently accepted that the human brain has a limited neurogenic capacity and an impaired regenerative potential. We have previously shown the existence of CD271-expressing neural stem cells (NSCs) in the subventricular zone (SVZ) of Parkinson’s disease (PD) patients, which proliferate and differentiate towards neurons and glial cells in vitro. To study the molecular profile of these NSCs in detail, we performed RNA sequencing and mass spectrometry on CD271+ NSCs isolated from human post-mortem SVZ and on homogenates of the SVZ. CD271+ cells were isolated through magnetic cell separation (MACS). We first compared the molecular profile of CD271+ NSCs to the SVZ homogenate from control donors to assess the CD271+ NSCs gene signature and finally made a comparison between controls and PD patients to establish a specific molecular profile of NSCs and the SVZ in PD. While our transcriptome analysis did not identify any differentially expressed genes in the SVZ between control and PD patients, our proteome analysis revealed several proteins that were differentially expressed in PD. Some of these proteins are involved in cytoskeletal organization and mitochondrial function. Transcriptome and proteome analyses of NSCs from PD revealed changes in the expression of genes and proteins involved in metabolism, transcriptional activity and cytoskeletal organization. Our results not only confirm pathological hallmarks of PD (e.g. impaired mitochondrial function), but also suggest that NSCs may transit into a primed-quiescent state, that is in an “alert” non-proliferative phase in PD.

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Histone lysine demethylase JMJD3/KDM6B is required for the establishment of adult hippocampal neurogenesis

Project description:Mutations in the JMJD3 (KDM6B) chromatin regulator are causally associated with autism spectrum disorder and syndromic intellectual disability, but the neurodevelopmental roles of this histone 3 lysine 27 (H3K27) demethylase are poorly understood. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) generate new granule neurons throughout life, and deficits in DG neurogenesis are associated with cognitive and behavioral problems. Here we show that Jmjd3 is required for the establishment of adult neurogenesis in the mouse DG. Conditional deletion of Jmjd3 in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs. While early postnatal mice with Jmjd3-deletion have near normal numbers of DG NSCs, at later stages, Jmjd3-deleted NSCs fail to propagate normally. In addition to the loss of NSCs during postnatal development, neurogenesis from Jmjd3-deleted NSCs is impaired, corresponding to defective neurogenic gene expression. Without Jmjd3, NeuroD2 and Bcl11b(Ctip2) are not properly expressed and exhibit increased levels of H3K27me3, underscoring the role of Jmjd3 in the regulation of transcription for neuronal differentiation. Thus, these data indicate that Jmjd3 plays dual roles in postnatal DG neurogenesis, being critical for the establishment of the NSC pool as well as the differentiation of young DG granule neurons. More broadly, our results suggest a neurodevelopmental link between JMJD3 mutations and hippocampal dysfunction, providing new insights into how mutations in chromatin regulators may contribute to learning disorders.

2021-04-01 | GSE73706 | GEO

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