Glial-Specific Functions of Microcephaly Protein WDR62 and Interaction with the Mitotic Kinase AURKA Are Essential for Drosophila Brain Growth

The second most commonly mutated gene in primary microcephaly (MCPH) patients is wd40-repeat protein 62 (wdr62), but the relative contribution of WDR62 function to the growth of major brain lineages is unknown. Here, we use Drosophila models to dissect lineage-specific WDR62 function(s). Interestingly, although neural stem cell (neuroblast)-specific depletion of WDR62 significantly decreased neuroblast number, brain size was unchanged. In contrast, glial lineage-specific WDR62 depletion significantly decreased brain volume. Moreover, loss of function in glia not only decreased the glial population but also non-autonomously caused neuroblast loss. We further demonstrated that WDR62 controls brain growth through lineage-specific interactions with master mitotic signaling kinase, AURKA. Depletion of AURKA in neuroblasts drives brain overgrowth, which was suppressed by WDR62 co-depletion. In contrast, glial-specific depletion of AURKA significantly decreased brain volume, which was further decreased by WDR62 co-depletion. Thus, dissecting relative contributions of MCPH factors to individual neural lineages will be critical for understanding complex diseases such as microcephaly. [Display omitted] •Glial-specific depletion of microcephaly protein WDR62 impairs brain growth•wdr62 depletion in glia causes neural stem cell (NSC) loss•WDR62 is required cell extrinsically in the NSC niche•Lineage-specific interactions between WDR62 and AURKA control brain growth Quinn and colleagues use Drosophila models to demonstrate that depletion of microcephaly protein WDR62 specifically in the glial lineage impairs brain growth. Moreover, wdr62 depletion in glia not only impairs brain growth by decreasing the glial population but also leads to neural stem cell (NSC) loss. Thus, MCPH proteins are essential not only intrinsically for glial cell proliferation but are also required cell extrinsically for establishing the NSC niche.