Epigenetic Regulation of miR-184 by MBD1 Governs Neural Stem Cell Proliferation and Differentiation

• DOI: 10.1016/j.stem.2010.02.017
• Publication Date: 2010-05-07T11:54:26Z
• Authors: Changmei Liu; Zhao-Qian Teng; Nicholas J. Santi...; Keith E. Szulwach; Weixiang Guo; Peng Jin; Xinyu Zhao
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; Stem Cells; Intracellular Signaling Peptides and Proteins; Cell Differentiation; Nerve Tissue Proteins; Cell Biology; STEMCELL; Epigenesis, Genetic; DNA-Binding Proteins; Adult Stem Cells; Mice; MicroRNAs; 03 medical and health sciences; Genetics; Molecular Medicine; Animals; Cell Proliferation

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.