Elevated IKK? accelerates the differentiation of human neuronal progenitor cells and induces MeCP2-dependent BDNF expression.

ABSTRACT: The I?B kinase ? (IKK?) is implicated in the differentiation of epithelial and immune cells. We examined whether IKK? also plays a role in the differentiation and maturation of embryonic human neuronal progenitor cells (NPCs). We find that expression of an extra copy of IKK? (IKK?+) blocks self-renewal and accelerates the differentiation of NPCs. This coincides with reduced expression of the Repressor Element Silencing Transcription Factor/Neuron-Restrictive Silencing Factor (REST/NRSF), which is a prominent inhibitor of neurogenesis, and subsequent induction of the pro-differentiation non-coding RNA, miR-124a. However, the effects of IKK? on REST/NRSF and miR-124a expression are likely to be indirect. IKK?+ neurons display extensive neurite outgrowth and accumulate protein markers of neuronal maturation such as SCG10/stathmin-2, postsynaptic density 95 (PSD95), syntaxin, and methyl-CpG binding protein 2 (MeCP2). Interestingly, IKK? associates with MeCP2 in the nuclei of human neurons and can phosphorylate MeCP2 in vitro. Using chromatin immunoprecipitation assays, we find that IKK? is recruited to the exon-IV brain-derived neurotrophic factor (BDNF) promoter, which is a well-characterized target of MeCP2 activity. Moreover, IKK? induces the transcription of BDNF and knockdown expression of MeCP2 interferes with this event. These studies highlight a role for IKK? in accelerating the differentiation of human NPCs and identify IKK? as a potential regulator of MeCP2 function and BDNF expression.

SUBMITTER: Khoshnan A 

PROVIDER: S-EPMC3407048 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature