Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation

Cell Stem Cell. 2010 May 7;6(5):433-44. doi: 10.1016/j.stem.2010.02.017.

Abstract

Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism. We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear. Here, we show that MBD1 regulates the expression of several microRNAs in aNSCs and, specifically, that miR-184 is directly repressed by MBD1. High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency. We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3'-UTR of Numbl mRNA and affecting its translation. Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency. Therefore, MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / metabolism
  • Animals
  • Cell Differentiation*
  • Cell Proliferation
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic*
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Neurons / metabolism
  • Stem Cells / cytology*
  • Stem Cells / metabolism*

Substances

  • DNA-Binding Proteins
  • MIRN184 microRNA, mouse
  • Mbd1 protein, mouse
  • MicroRNAs
  • Nerve Tissue Proteins
  • Numbl protein, mouse