Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Cell Stem Cell. 2010 May 7;6(5):433-44. doi: 10.1016/j.stem.2010.02.017.
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.
甲基化 CpG 结合蛋白 1（MBD1）通过 DNA 甲基化介导的表观遗传机制调节基因表达。我们之前已经证明，MBD1 缺乏会损害成体神经干细胞/祖细胞（aNSC）的分化和神经发生，但潜在的机制尚不清楚。在这里，我们表明 MBD1 调节 aNSC 中几种 microRNA 的表达，并且 miR-184 是直接受到 MBD1 抑制的。高水平的 miR-184 促进了 aNSC 的增殖但抑制了分化，而抑制 miR-184 则挽救了与 MBD1 缺乏相关的表型。我们进一步发现，miR-184 通过结合 Numbl mRNA 的 3'-UTR 并影响其翻译来调节 Numblike（Numbl）的表达，Numbl 是已知的脑发育调节剂。外源性 Numbl 的表达可以挽救由 miR-184 过表达或 MBD1 缺乏引起的 aNSC 缺陷。因此，MBD1、miR-184 和 Numbl 形成了一个调节网络，有助于控制 aNSC 增殖和分化之间的平衡。
