Mutations　of　WD　repeat　domain　62　(WDR62)　lead　to　autosomal　recessive　primary　microcephaly　(MCPH),　and　down-regulation　of　WDR62　expression　causes　the　loss　of　neural　progenitor　cells　(NPCs).　However,　how　WDR62　is　regulated　and　hence　controls　neurogenesis　and　brain　size　remains　elusive.　Here,　we　demonstrate　that　mitogen-activated　protein　kinase　kinase　kinase　3　(MEKK3)　forms　a　complex　with　WDR62　to　promote　c-Jun　N-terminal　kinase　(JNK)　signaling　synergistically　in　the　control　of　neurogenesis.　The　deletion　of　Mekk3,　Wdr62,　or　Jnk1　resulted　in　phenocopied　defects,　including　premature　NPC　differentiation.　We　further　showed　that　WDR62　protein　is　positively　regulated　by　MEKK3　and　JNK1　in　the　developing　brain　and　that　the　defects　of　wdr62　deficiency　can　be　rescued　by　the　transgenic　expression　of　JNK1.　Meanwhile,　WDR62　is　also　negatively　regulated　by　T1053　phosphorylation,　leading　to　the　recruitment　of　F-box　and　WD　repeat　domain-containing　protein　7　(FBW7)　and　proteasomal　degradation.　Our　findings　demonstrate　that　the　coordinated　reciprocal　and　bidirectional　regulation　among　MEKK3,　FBW7,　WDR62,　and　JNK1,　is　required　for　fine-tuned　JNK　signaling　for　the　control　of　balanced　NPC　self-renewal　and　differentiation　during　cortical　development.　©　2018　Xu　et　al.　http://creativecommons.org/licenses/by/4.0/.