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A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex [ChIP-seq]

ABSTRACT: During development neural stem cells (NSCs) in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Shh signaling promotes cortical RGCs to switch lineage to generate cortical oligodendrocytes and OB interneurons. During this lineage switch, cortical RGCs generate intermediate progenitor cells (IPCs) that express Ascl1, Egfr and Olig2, genes critically regulating gliogenesis. The timing of increased Ascl1 expression and the appearance of Egfr+ and Olig2+ cortical progenitors is concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Further, the transcriptional regulation of Olig2 and Egfr has not been explored. Here we show that in cortical progenitor cells, multiple genetic programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple distal enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE254690 | GEO | 2024/05/02

REPOSITORIES: GEO

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A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex [CUT&RUN]

Project description:During development neural stem cells (NSCs) in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Shh signaling promotes cortical RGCs to switch lineage to generate cortical oligodendrocytes and OB interneurons. During this lineage switch, cortical RGCs generate intermediate progenitor cells (IPCs) that express Ascl1, Egfr and Olig2, genes critically regulating gliogenesis. The timing of increased Ascl1 expression and the appearance of Egfr+ and Olig2+ cortical progenitors is concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Further, the transcriptional regulation of Olig2 and Egfr has not been explored. Here we show that in cortical progenitor cells, multiple genetic programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple distal enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

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Project description:Generation of olfactory bulb (OB) interneurons requires neural stem/progenitor cell specification, proliferation, differentiation, and young interneuron migration and maturation. Here, we show that the homeobox transcription factors Dlx1/2 are central and essential components in the transcriptional code for generating OB interneurons. In Dlx1/2 constitutive null mutants, the differentiation of GSX2+ and ASCL1+ neural stem/progenitor cells in the dorsal lateral ganglionic eminence is blocked, resulting in a failure of OB interneuron generation. In Dlx1/2 conditional mutants (hGFAP-Cre; Dlx1/2F/- mice), GSX2+ and ASCL1+ neural stem/progenitor cells in the postnatal subventricular zone also fail to differentiate into OB interneurons. In contrast, overexpression of Dlx1&2 in embryonic mouse cortex led to ectopic production of OB-like interneurons that expressed Gad1, Sp8, Sp9, Arx, Pbx3, Etv1, Tshz1 and Prokr2. Pax6 mutants generate cortical ectopia with OB-like interneurons, but do not do so in compound Pax6; Dlx1/2 mutants. We propose that DLX1/2 promote OB interneuron development mainly through activating the expression of Sp8/9, which further promote Tshz1 and Prokr2 expression. Based on this study, in combination with earlier ones, we propose a transcriptional network for the process of OB interneuron development. This SuperSeries is composed of the SubSeries listed below.

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epigenetic control of neurogenesis-to-gliogenesis switch during mouse cortical development

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CCN1 forms a complex with GPC4 and heparin to fine tune signaling activities for embryonic cortical neural stem cell maintenance

Project description:Radial glial cells (RGCs) are the neural stem cells (NSCs) in the developing brain, capable of self-renewing and generating neurons and glia in order. The developmental behaviors of NSCs are determined by extrinsic factors from the NSC niche, together with intrinsic factors. Here, we show that Cellular Communication Network 1 (CCN1), a secreted matricellular protein, is an autocrine factor derived from RGCs in the embryonic telencephalon. Loss of Ccn1 in RGCs leads to accelerated lineage progression of RGCs, and causes premature cell cycle exit and neuronal differentiation, resulting in a reduction in NSC pool size, disruption of the cortical projection neurons generation, and in turn, at the expense of the perinatal gliogenesis. Mechanistically, CCN1 interacts with an RGC-expressed membrane protein GPC4, one of the heparan sulfate proteoglycans (HSPGs), and is required for GPC4 to maintain NSCs through the Sonic Hedgehog (Shh) signaling pathway, depending on the binding of heparin to CCN1. Our work provides a potential mechanism for the dynamic and sophisticated interconnections of niche components that meet the needs of context-dependent maintenance, differentiation, and fate determination of NSCs.

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Project description:The Outer Subventricular Zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species like human and ferret where it contains abundant basal Radial Glia Cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident down-regulation of Cdh1 and Trnp1, and their up-regulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease Samples were analyzed with 3 replicates of each of them (except E34SVZ that has 2 replicantes). Comparisons were done taking different reference sample depending on the comparison.

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