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PROVIDER: PRJNA1236627 | ENA |
REPOSITORIES: ENA
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Project description:Voltage-gated sodium channels regulate neuronal excitability and fast synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD). The expression pattern of SCN2A begins during fetal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated sonic hedgehog (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity. Our results identify a new mechanisim for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precedes postnatal neural circuit dysfunction in SCN2A-associated disorders.
2026-06-09 | GSE292644 | GEO
Project description:Scn2a encodes voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs excitability contributing to autism. This paradigm, however, does not explain why 20~30% of patients with NaV1.2 deficiency still develop seizures. Here we report a counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a unique NaV1.2-deficient mouse model, we found enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by the genetic restoration of Scn2a expression in adult mice. RNA-sequencing revealed that the downregulation of multiple potassium channels including KV1.1, and KV channel openers alleviated hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures.
2021-07-13 | GSE179818 | GEO
Project description:Cell differentiation and proliferation are mutually exclusive. Although differentiating neurons are recognized as post-mitotic non-dividing cells, some Rb- and Rb family (Rb, p107, and p130)-deficient differentiating neurons proliferate and form tumor. Here, we found that the acute inactivation of all Rb family in differentiating cortical excitatory neurons caused radial migration defect and S-phase progression but not cell division, whereas that in cortical progenitors caused the cell division of the differentiating neurons generated from Rb –/–; p107 –/–; p130 –/– (Rb-TKO) progenitors. Genome-wide DNA methylation analysis revealed that proximal promoters tended to become methylated during differentiation in vivo. DNA demethylation by DNA methyltransferase inhibitor allowed the acutely inactivated Rb-TKO differentiating neurons to undergo G2/M-phase progression. Our finding illustrate that cortical excitatory neurons epigenetically lose their proliferative potency after neurogenesis. 1 sample of the V/SVZ tissue and the CP tissue
2014-01-01 | E-GEOD-37601 | biostudies-arrayexpress
Project description:MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders
| PRJNA343877 | ENA
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.
2024-05-06 | GSE254692 | GEO
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.
2024-05-06 | GSE254691 | GEO
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.
2024-05-02 | GSE254690 | GEO
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.
2024-05-06 | GSE254689 | GEO
Project description:The cerebral cortex comprises diverse excitatory and inhibitory neuron subtypes, each with distinct laminar positions and connectivity patterns. Yet, the molecular logic underlying their precise wiring remains poorly understood. To identify ligand–receptor (LR) interactions involved in cortical circuit assembly, we tracked gene expression dynamics across major neuronal populations at 17 developmental stages using single-cell transcriptomics. This generated a comprehensive atlas of LR-mediated communication between excitatory and inhibitory neuron subtypes, capturing known and novel interactions. Notably, we identify neogenin-1 as the principal receptor for Cbln4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons. We also identify cadherin superfamily members as candidate regulators of perisomatic inhibition onto deep and superficial excitatory neurons by parvalbumin-expressing basket cells, with opposing effects on synapse formation. These findings suggest a context-dependent role for cadherins in synaptic specificity and underscore the power of single-cell transcriptomics for decoding molecular mechanisms of cortical wiring.
2026-01-30 | E-MTAB-16260 | biostudies-arrayexpress