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 and 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 generate Wdr62 deficient mice which exhibit reduced brain size.We demonstrate that WDR62 controls neurogenesis through a novel protein complex including WDR62,MEKK3,MKKs and JNK1.MEKK3,WDR62 and JNK1 depletion or deficiency phenocopy each other in defects including premature differentiation of NPCs.WDR62 and MEKK3 regulates each others stability and JNK activity synergistically.In addition,we find that the stability of WDR62 is negatively regulated by an E3 ligase through the proteasomal pathway.Our findings demonstrate that WDR62 is required for the maintenance of NPC via MEKK3 and JNK1 and disclose the molecular mechanisms underlying MCPH pathogenesis.