Neocortical projection neurons instruct inhibitory interneuron circuit development in a lineage dependent manner
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PROVIDER: PRJNA525662 | ENA |
REPOSITORIES: ENA
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Project description:Neocortical circuits consist of stereotypical motifs that must self-assemble during development. Recent evidence suggests the subtype identity of both excitatory projection neurons (PNs) and inhibitory interneurons (INs) is important for this process. We knocked out the transcription factor Satb2 in PNs to induce those of the intratelencephalic (IT)-type to adopt a pyramidal tract (PT)-type identity. Loss of IT-type PNs selectively disrupted the lamination and circuit integration of INs derived from the caudal ganglionic eminence (CGE). Strikingly, reprogrammed PNs demonstrated reduced synaptic targeting of CGE-derived INs relative to controls. In control mice, IT-type PNs targeted neighboring CGE INs while PT-type PNs did not in deep layers, confirming this lineage-dependent motif. Finally, single cell RNA-sequencing revealed that major CGE IN subtypes were conserved after loss of IT PNs, but with differential transcription of synaptic proteins and signaling molecules. Thus, IT-type PNs influence CGE-derived INs in a non-cell autonomous manner during cortical development.
2019-03-06 | GSE127724 | GEO
Project description:Subtypes of neocortical projection neurons over developmental time
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Project description:Variation in activity state, axonal projection, and position define the transcriptional identity of individual neocortical projection neurons.
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Project description:Intrinsic molecular pathways in the central nervous system dictate neuronal cell fate during development. However, interplay of RNA binding proteins (RBPs) dictating mRNA translation, and their spatiotemporal extracellular regulators in neocortical neural stem cells during neurogenesis are poorly understood. Using an unbiased RNAseq screen of polysomes between early and mid-neurogenesis, we identified functionally related mRNA groups and their isoforms are regulated translationally in prenatal neocortices, including mRNAs encoding RBPs. Here, we show that isoforms of the RBP, Hu antigen D (HuD), regulate the balance of neocortical glutamatergic neurons in an isoform-specific manner during development. HuD3 promoted a Cdp+ intracortically projecting neuronal fate, while HuD4 promoted a Tle4+ subcortically projecting neuronal fate. In early neurogenic radial glia of the neocortex, HuD transcripts were bound and translationally repressed by another RBP, CUG triplet repeat RNA-binding protein 1 (Cugbp1). Cugbp1 knockdown increased the number of Cdp+ intracortically projecting neurons, while having distinct effects on Tle4+ and Ctip2+ subcortically projecting neurons. Neurotrophin-3 promoted HuD3 mRNA translation and Cdp+ fate, which was reversed by Cugbp1. Thus, our findings reveal a novel post-transcriptional molecular pathway in the developing neocortex that regulates the balance of distinct subpopulations of neocortical projection neurons.
2017-09-08 | GSE77647 | GEO
Project description:Forkhead-box domain (Fox) containing family members are known autism spectrum associated genes. Here we show that, within the developing neocortex, the distinct phospho-states of a single RNA-binding protein, Hu antigen R, dictate mRNA translation and are sufficient to define distinct Foxp-characterized subpopulations of neocortical projection neurons. This demonstrates the importance of HuR phospho-states within the framework of the developing brain and further confirms the role of mRNA translation in autism pathogenesis.
2016-07-08 | GSE77712 | GEO
Project description:The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.
2024-02-19 | GSE231774 | GEO
Project description:Interneurons navigate along multiple tangential paths to settle into appropriate cortical layer. They undergo saltatory migration, which is paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. However, it remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes deglutamylation, is a pivotal regulator of pausing of cortical interneurons. Moreover, we show that pausing during migration controls the flow of interneurons invading the cortex by generating heterogeinity in movement at the population level. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also secondarily impairs the generation of age-matched upper layer projection neurons.
2018-02-14 | PXD006397 | Pride
Project description:Neuronal cell types are classically defined by their molecular properties, anatomy, and functions. While recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To better understand the relationship between molecular and anatomical features defining cortical neurons, we developed Epi-Retro-Seq, a method that combined retrograde labeling with single-nucleus DNA methylation sequencing to link epigenomic properties of cell types to neuronal projections. We profiled 16,971 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results revealed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. The methylomes of 16,971 mouse neocortical neurons from 63 cortico-cortical (CC) and cortico-subcortical long-distance projections were analyzed using Epi-Retro-Seq, a method that combined retrograde tracing and single nucleus methylome sequencing.
2020-11-16 | GSE150170 | GEO
Project description:Gene regulatory elements such as enhancers dynamically regulate gene expression in a tissue-specific manner. However, the transcriptional regulatory elements during human inhibitory interneuron differentiation and their role in neurodevelopmental disorders are unknown. Here, we generate gene regulatory element maps of human inhibitory-like interneurons derived from embryonic stem cells (H9-ESC), permitting large-scale annotation of previously uncharacterized regulatory elements relevant to inhibitory interneuron differentiation. Our analyses identify neuronal progenitor enhancers that likely regulate the expression of transcription factors that are essential for interneuron differentiation. Focusing on dynamic changes in chromatin organization, FOXG1 and ZEB2, where the chromatin organization is changed in interneuron progenitors compared to different stages during the differentiation. Using 4C-seq and an in vivo enhancer assay, we characterized neuronal enhancers at the FOXG1 locus that interact with the FOXG1 promoter region and showed activity patterns that resemble FOXG1 expression. Using CRISPR/Cas9 genome editing, we deleted FOXG1 enhancer/s that reduced FOXG1 expression in glioblastoma cells and altered cell proliferation. Furthermore, a microdeletion proximal to FOXG1 encompassing these neuronal FOXG1 enhancers was found in a patient with Rett-like syndrome, supporting the role of FOXG1 enhancers in this syndrome. Thus, our study elucidates the gene regulatory networks of human inhibitory interneurons. Furthermore, it provides a framework for understanding the impact of non-coding regulatory elements during inhibitory interneuron differentiation, and highlights novel mechanisms underlying neurodevelopmental disorders.
2023-03-15 | GSE218668 | GEO
Project description:Single-cell RNA sequencing has generated the first catalogs of transcriptionally defined neuronal subtypes of the brain. However, the cellular processes that contribute to neuronal subtype specification and transcriptional heterogeneity remain unclear. By comparing the gene expression profiles of a subset of single layer 6 corticothalamic neurons in somatosensory cortex, we show that transcriptional subtypes primarily reflect axonal projection pattern, laminar position within the cortex, and neuronal activity state. Pseudotemporal ordering of 1023 cellular responses to sensory manipulation demonstrates that changes in expression of activity-induced genes both reinforced cell-type identity and contributed to increased transcriptional heterogeneity within each cell type. This is due to cell-type biased choices of transcriptional states following manipulation of neuronal activity. These results reveal that axonal projection pattern, laminar position, and activity state define significant axes of variation that contribute both to the transcriptional identity of individual neurons and to the transcriptional heterogeneity within each neuronal subtype.
2017-12-31 | GSE107632 | GEO