Microcephaly-Associated Protein WDR62 Regulates Neurogenesis through JNK1 in the Developing Neocortex

Abstract

Mutations of WD40-repeat protein 62 (WDR62) have been identified recently to cause human MCPH (autosomal-recessive primary microcephaly), a neurodevelopmental disorder characterized by decreased brain size. However, the underlying mechanism is unclear. Here, we investigate the function of WDR62 in brain development and the pathological role of WDR62 mutations. We find that WDR62 knockdown leads to premature differentiation of neural progenitor cells (NPCs). The defect can be rescued by wild-type human WDR62, but not by the five MCPH-associated WDR62 mutants. We demonstrate that WDR62 acts upstream of JNK signaling in the control of neurogenesis. Depletion of JNK1 and WDR62 incurs very similar defects including abnormal spindle formation and mitotic division of NPCs as well as premature NPC differentiation during cortical development. Thus, our findings indicate that WDR62 is required for proper neurogenesis via JNK1 and provide an insight into the molecular mechanisms underlying MCPH pathogenesis.

Aurora A phosphorylation of WD40-repeat protein 62 in mitotic spindle regulation

“…[16][17][18] In support of a requirement for WDR62 in mammalian brain development, the depletion of WDR62 decreased mouse brain volume, reduced the proliferation of neural progenitor cells (NPCs) and increased spindle instability. 19,20 Similarly, in utero depletion of WDR62 in embryonic mouse brain also caused premature differentiation of NPCs into immature neurons. 19,21 In characterizing the mitotic functions of WDR62, the ectopic expression of mutant proteins recapitulating MCPH-associated gene changes resulted in perturbed localization to the spindle pole which suggests that the localization of WDR62 and its interacting partners at spindle poles is important for normal mitosis.…”

“…19,20 Similarly, in utero depletion of WDR62 in embryonic mouse brain also caused premature differentiation of NPCs into immature neurons. 19,21 In characterizing the mitotic functions of WDR62, the ectopic expression of mutant proteins recapitulating MCPH-associated gene changes resulted in perturbed localization to the spindle pole which suggests that the localization of WDR62 and its interacting partners at spindle poles is important for normal mitosis. 16,22 WDR62 was first characterized as an interacting partner of c-Jun N-terminal kinases (JNK) involved in regulating stress signaling.…”

Driving WDR62 to the pole

“…JNK signaling, together with WDR62, has been shown previously to take part in the control of neurogenesis 5 and JNK-mediated phosphorylation of WDR62 in the C-terminal negatively regulated its microtubule association. 6 The authors showed in this study that JNK-mediated phosphorylation of WDR62 may not be required for the mitotic localization of WDR62.…”

“…The authors adopted CRISPR technique to generate WDR62 ko AD293 cells and found in them the multipolar spindles, abnormal spindle morphology as reported for WDR62 knockdown and knockout in neuronal progenitors. 4,5 Interestingly, wildtype WDR62, but not those defective in AURKA-dependent phosphorylation can rescue the mitotic defects. In addition, AURKA mainly phosphorylates WDR62 at the N-terminal in M phase.…”

“…1 Most primary autosomal recessive microcephaly-associated (MCPH) proteins including WDR62 are related to centrosome or spindle pole and essential for spindle pole formation and neurogenesis during brain development. [2][3][4][5] WDR62 is diffused in cytoplasm in the interphase and accumulates strongly at the spindle poles during mitosis. 2,3,5,6 Little is known regarding the mechanisms that determine the cell cycle-dependent spatiotemporal distribution of WDR62.…”