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

Abstract

SummaryThe 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.

JNK-mediated spindle reorientation in stem cells promotes dysplasia in the aging intestine

“…The role of Wdr62 in stem cell activity has previously been characterized in the developing brain (Bogoyevitch et al, 2012;Jayaraman et al, 2016;Lim et al, 2017;Nicholas et al, 2010;Ramdas Nair et al, 2016;Shohayeb et al, 2017;Xu et al, 2014;Yu et al, 2010), and our study marks the first study supporting a role of Wdr62 in spindle orientation of adult, non-neuronal stem cells. Mutations in Wdr62 are a hallmark of microcephaly, where the developing brain fails to reach its proper size because stem cell production is stunted (Bilgüvar et al, 2010;Nicholas et al, 2010;Yu et al, 2010).…”

“…Wdr62 is a centrosome-associated protein and a phosphorylation target of JNK (Bogoyevitch et al, 2012;Cohen-Katsenelson et al, 2011;Williams et al, 2011;Williams et al, 2014). Loss of Wdr62 was reported to cause cell fate defects in both Drosophila and mammalian neural stem cells (Jayaraman et al, 2016;Lim et al, 2017;Ramdas Nair et al, 2016;Xu et al, 2014), but the role of Wdr62 on spindle orientation has yet to be examined in non-neuronal tissue. Given the observed role for JNK in regulating ISC spindle orientation, we tested whether Wdr62 would also influence spindle orientation in these cells.…”

The UFM1 cascade times mitosis entry associated with microcephaly

“…[28][29][30][31] The genes causing microcephaly have been widely acknowledged to link closely to the mitotic apparatus that take part in DNA replication, centriole duplication, chromosome condensation, spindle assembly, and mitotic checkpoint activation. [33][34][35][36] In this study, we observed that knockdown of the UFM1 cascade in Drosophila neuroblasts (NB) reduced the number of NBs and brain size, mimicking microcephaly that is found in humans. [33][34][35][36] In this study, we observed that knockdown of the UFM1 cascade in Drosophila neuroblasts (NB) reduced the number of NBs and brain size, mimicking microcephaly that is found in humans.…”

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…MCPH1 (BRIT1) CHK1, CDC25, CDK1 [16] SLUG, CDK1, p53, CDH1, MDM2, SNAIL [42] p53 [110] CyclinA2, CDK2, CDC25C-cyclinB, CDC2, p53, BCL-2, Bax, Cytochrome c, Caspase-3, PARP-1 [40] MCPH2 (WDR62) JNK [18] N/A AURKA [119] PLK1 [43] MCPH3 (CDK5RAP2) p35 [120] N/A MST1, TAZ (Hippo) [121] MCPH4 (CASC5) BUB1, BUBR, ZWINT-1 [122] BUB1 [52] miR-193b-3p [27] p53 [123] MCPH5 (ASPM) The p53 gene (TP53) is classified as a tumor suppressor gene, and upregulation of its activity led to neural progenitor apoptosis in MCPH gene-deficient mice. Deletion of Mcph5 increases DNA damage and induces postnatal cerebellar progenitor apoptosis that depends on p53 [114].…”