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

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. © 2017 moon et al.