Zhiheng Xu
Chinese Academy of Sciences, China
Title: MEKK3 coordinates with FBW7 to regulate microcephaly associated protein WDR62 and neurogenesis
Biography
Biography: Zhiheng Xu
Abstract
Human autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder hallmarked by significantly reduced brain size and variable intellectual disability. Mutation of WD40-repeat protein 62 (WDR62) is the second major cause of MCPH. We have reported recently that WDR62 regulates the maintenance of neural progenitor cells (NPCs) during cortical development through JNK1 (Xu et al., Cell Reports 2014). However, the detailed biological function of WDR62 and the underlying mechanism by which WDR62 regulates JNK signaling are still not very clear. Here, we demonstrate that MEKK3 forms a complex with WDR62 to promote JNK signaling synergistically and regulate neurogenesis as well as brain size. MEKK3, WDR62 and JNK1 depletion or knockout phenocopy each other in defects including premature NPC differentiation and reduced brain size. These defects can be rescued by the expression of transgenic JNK1, indicating that the complex controls neurogenesis through JNK signaling. We show further that WDR62 protein level is positively regulated by MEKK3 through JNK1-induced WDR62 phosphorylation. Meanwhile, WDR62 is also negatively regulated by specific phosphorylation of WDR62 at T1053, leading to the recruitment of the E3 ligase FBW7 and proteasomal degradation of WDR62. Our findings demonstrate that WDR62 controls the maintenance of NPCs via MEKK3 and JNK1 during cortical development and reveal the molecular mechanisms underlying MCPH pathogenesis.
