Elevated IKKα Accelerates the Differentiation of Human Neuronal Progenitor Cells and Induces MeCP2-Dependent BDNF Expression

The I kappa B kinase alpha (IKK alpha) is implicated in the differentiation of epithelial and immune cells. We examined whether IKK alpha 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 alpha (IKK alpha+) 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 alpha on REST/NRSF and miR-124a expression are likely to be indirect. IKK alpha+ 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 alpha associates with MeCP2 in the nuclei of human neurons and can phosphorylate MeCP2 in vitro. Using chromatin immunoprecipitation assays, we find that IKK alpha is recruited to the exon-IV brain-derived neurotrophic factor (BDNF) promoter, which is a well-characterized target of MeCP2 activity. Moreover, IKK alpha induces the transcription of BDNF and knockdown expression of MeCP2 interferes with this event. These studies highlight a role for IKK alpha in accelerating the differentiation of human NPCs and identify IKK alpha as a potential regulator of MeCP2 function and BDNF expression.