Smek promotes corticogenesis through regulating Mbd3's stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis

PLoS Biol. 2017 May 3;15(5):e2001220. doi: 10.1371/journal.pbio.2001220. eCollection 2017 May.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology*
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Developmental
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Mice, Knockout
  • Neural Stem Cells / physiology
  • Neurogenesis / genetics*
  • Neuroglia / physiology
  • Phosphoprotein Phosphatases / physiology*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Mbd3 protein, mouse
  • Transcription Factors
  • Phosphoprotein Phosphatases
  • Ppp4r3a protein, mouse
  • Smek2 protein, mouse
  • 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.