Driving WDR62 to the pole

Mitotic spindle organization is highly dynamic throughout the cell cycle and it is critical for successful mitosis in mammalian cells. Activated by TPX2 at the beginning of mitosis, the mitotic kinase Aurora A (AURKA) regulates spindle formation to ensure proper mitotic progression.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.^2-5 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.

The paper by Dominic Ng and colleagues elucidates the importance of TPX2 controlled AURKA activity in the regulation of spindle localization for WDR62.⁷ AURKA and WDR62 show very similar expression patterns during different cell cycle phases. The depletion of AURKA co-activator, TPX2, leads to decreased AURKA activity, arrest of cells in prometaphase and the defective recruitment of both AURKA and WDR62 to the spindle pole. 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, wild-type 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. Therefore, AURKA-directed mitotic phosphorylation of WDR62 determines WDR62's spindle localization and is critical for spindle alignment and mitotic integrity. More importantly, some MCPH-associated mutants are not localized to spindle pole.^2,3 Those mutants show reduced AURKA interaction and AURKA directed phosphorylation, as well as the mitotically-stimulated phosphorylation. This indicates that those mutants are associated with disrupted AURKA signaling to WDR62 and compromised spindle localization.

JNK signaling, together with WDR62, has been shown previously to take part in the control of neurogenesis⁵ 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. Therefore, JNK and AURKA directed phosphorylation of WDR62 at different sites, C- vs N-terminal, may play different roles in the regulation of WDR62 function at mitotic spindle and during brain development (Fig. 1). Although the exact mechanism of AURKA and JNK signaling in these processes remains to be unveiled, this study provides important clues toward our understanding of the underlying mechanisms for the regulation of mitotic spindle pole formation as well as the potential pathogenesis of microcephaly.

Figure 1.

TPX2 regulates AURKA activity to control WDR62 localization. During M Phase, TPX2 activates AURKA. AURKA phosphorylates WDR62 and contributes to their co-localization at mitotic spindle. AURKA and JNK phosphorylate WDR62 in the N-terminal (red) and C-terminal (black) respectively. In TPX2 knockdown cells, AURKA activity decreases, leading to the failed recruitment of WDR62 to the spindle pole.