SYM-05-05

Aurora A and WD40-Repeat protein 62 (WDR62) signalling regulation of cell cycle progression and normal brain growth

NR Lim1, B Shohayeb2, YY Yeap2, LM Quinn3 and DCH Ng1,2

  1. Department of Biochemistry and Molecular Biology, University of Melbourne
  2. School of Biomedical Science, University of Queensland
  3. Department of Anatomy and Neuroscience, University of Melbourne

The study of genetic mutations causative for primary microcephaly (reduced brain size) has informed on the molecular determinants of neuroprogenitor fate decisions required for normal growth, with broad implications in human disease including cancer and neurological disorders. The most commonly mutated microcephaly genes encode centrosome/spindle pole proteins including WD40-Repeat Protein 62 (WDR62), a signaling scaffold that organizes c-Jun N-terminal kinase (JNK) activity. Deletion of WDR62 in mice or orthologous genes in Drosophila and Zebrafish recapitulate the microcephaly phenotype indicating high functional conservation. However, the precise molecular mechanisms underlying WDR62 functions remain undefined. In combined in vitro and in vivo studies, we reveal that spatiotemporal regulation of WDR62/JNK by centrosomal Aurora A kinase is required for cell cycle progression and timely division of neuroprogenitor cells.WDR62 is rapidly mobilized from the cytoplasm to bind spindle microtubules specifically during prometaphase. We show that Aurora A activity recruits WDR62/JNK to the spindle pole during this time and this is critical for spindle orientation, mitotic progression and self-renewal of neuroprogenitors. WDR62 microcephaly mutants fail to localize to mitotic spindles, are refractory to AURKA signalling and do not rescue division defects which suggest that AURKA/WDR62 signaling deficits may underlie disease pathology in humans. In defining the constituents of the mitotic phosphorylation network regulated by the AURKA/WDR62/JNK signalling node, we utilized proximity-labelling mass spectrometry and quantitative phosphoproteomics with stable-isotope labelling to identify novel centrosomal and spindle-regulatory factors as mitotic targets. Thus, our study has defined a novel centrosomal signalling mechanism required for mitotic spindle regulation and embryonic brain growth.