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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE191109 | GEO | 2022/09/12

REPOSITORIES: GEO

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Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression.

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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression [neurons]

Project description:The generation of a correctly-sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb Repressive Complex 2 (PRC2) and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here we utilize Mosaic Analysis with Double Markers (MADM)-based single cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide mechanisms. In a broader context our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.

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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression [astro]

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Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression

Project description:Tissue-wide Genetic and Cellular Landscape Instructs the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression

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Project description:The TEAD family of transcription factors is best known as the DNA-binding factor in the Hippo pathway, where these factors act by interacting with transcriptional coactivators YAP and TAZ (YAP/TAZ). Despite the importance of the Hippo pathway, the in vivo functions of TEAD in mammals have not been well established. By comparing mouse mutants lacking TEAD1 and TEAD2 (TEAD1/2) with those lacking YAP/TAZ, we found that TEAD1/2 have both YAP/TAZ-dependent and YAP/TAZ-independent functions during ventral telencephalon development. TEAD1/2 loss and YAP/TAZ loss similarly disrupt neuroepithelial apical junctions. However, the impacts of their losses on progenitor lineage progression are essentially opposite: YAP/TAZ loss depletes early progenitors and increases later progenitors, consistent with their established function in promoting progenitor self-renewal and proliferation, whereas TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote lineage progression. We further show that TEAD1/2 promote neural progenitor lineage progression by at least in part inhibiting Notch signaling and by cooperating with insulinoma-associated 1 (INSM1). Orthologs of TEAD and INSM1 have been shown to cooperatively regulate neuronal cell fate decisions in worms and flies. Our study reveals a remarkable evolutionary conservation of the function of this transcription factor complex during metazoan neural development.

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