Characterization of the microcephaly gene wd40-repeat protein 62 (wdr62) in brain growth and development

WD40-repeat protein 62 (WDR62) is a centrosome/microtubule-associated protein that is frequently mutated in primary microcephaly (MCPH). WDR62 has been implicated in centrosome biogenesis and spindle regulation; reinforcing the critical contribution of these processes towards carefully co-ordinated neural stem cell self-renewal, differentiation and neuronal migration in the expanding neocortex during development. It remains to be seen whether the range of neuronal and cellular deficits observed in animals lacking WDR62 is recapitulated with specific WDR62 missense mutations that retain protein expression. In this study, we characterized novel mouse models that recapitulate patient-identified missense mutations of WDR62 (V66M and R439H). Our results showed that V66 and R439 residues are essential to maintain self-renewal and timely neuronal differentiation during early brain development. In addition, these missense mutations caused defects in ciliogenesis in neural stem cells during early neural development. These ciliary defects resulted from a disruption in CPAP recruitment at the basal body, which is required for intra-ciliary transport of tubulin, and may contribute towards the aetiology of MCPH2. To further unravel the genetic complexity of MCPH2, we studied WDR62 functions in specific brain lineages using the power of Drosophila genetics. Unlike neural lineages, depletion of WDR62 in glia cells resulted in more severe brain growth defects causing smaller brain sizes. We also revealed a genetic interaction between WDR62 and AURKA, indicating that they act in concert in glia cells to non-autonomously promote neuroblast proliferation and brain growth. In contrast, the ectopic expression of Drosophila WDR62 in neural lineages is sufficient to promote brain overgrowth mediated through AURKA and PI3K/AKT/Myc signalling. Taken altogether, these results have provided new insights into the molecular regulation and function of WDR62 in neural stem cells and glia that are required for normal brain growth.