Abstract
The fate of neural progenitor cells (NPCs) during corticogenesis is determined by a complex interplay of genetic or epigenetic components, but the underlying mechanism is incompletely understood. Here, we demonstrate that Suppressor of Mek null (Smek) interact with methyl-CpG-binding domain 3 (Mbd3) and the complex plays a critical role in self-renewal and neuronal differentiation of NPCs. We found that Smek promotes Mbd3 polyubiquitylation and degradation, blocking recruitment of the repressive Mbd3/nucleosome remodeling and deacetylase (NuRD) complex at the neurogenesis-associated gene loci, and, as a consequence, increasing acetyl histone H3 activity and cortical neurogenesis. Furthermore, overexpression of Mbd3 significantly blocked neuronal differentiation of NPCs, and Mbd3 depletion rescued neurogenesis defects seen in Smek1/2 knockout mice. These results reveal a novel molecular mechanism underlying Smek/Mbd3/NuRD axis-mediated control of NPCs' self-renewal and neuronal differentiation during mammalian corticogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / embryology*
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Cell Differentiation
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Cells, Cultured
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Developmental
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
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Mice, Knockout
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Neural Stem Cells / physiology
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Neurogenesis / genetics*
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Neuroglia / physiology
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Phosphoprotein Phosphatases / physiology*
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Transcription Factors / metabolism*
Substances
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DNA-Binding Proteins
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Mbd3 protein, mouse
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Transcription Factors
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Phosphoprotein Phosphatases
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Ppp4r3a protein, mouse
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Smek2 protein, mouse
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Mi-2 Nucleosome Remodeling and Deacetylase Complex
Grants and funding
California Institute for Regenerative Medicine (CIRM)
https://www.cirm.ca.gov/grants (grant number TG2-01161). Received by BSM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institutes of Health
https://www.nih.gov/grants-funding (grant number 5R01NS06721305). Received by WL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.