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

Stem Cell Reports. 2017 Jul 11;9(1):32-41. doi: 10.1016/j.stemcr.2017.05.015. Epub 2017 Jun 15.

Abstract

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.

Keywords: AURKA; Drosophila; WD-repeat protein; WDR62; brain; glia; microcephaly; mitosis; neuroblast.

MeSH terms

  • Animals
  • Aurora Kinase A / genetics
  • Aurora Kinase A / metabolism*
  • Brain / growth & development*
  • Brain / metabolism
  • Drosophila / genetics
  • Drosophila / growth & development*
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gene Knockdown Techniques
  • Mitosis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuroglia / cytology
  • Neuroglia / metabolism*
  • Protein Interaction Maps*

Substances

  • Drosophila Proteins
  • Nerve Tissue Proteins
  • Wdr62 protein, Drosophila
  • Aurora Kinase A