WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

Meghna Kannan, Efil Bayam, Christel Wagner, Bruno Rinaldi, Perrine F. Kretz, Peggy Tilly, Marna Roos, Lara McGillewie, Séverine Bär, Shilpi Minocha, Claire Chevalier, Chrystelle Po, Valerie E. Vancollie, Lauren F.E. Anthony, Simon A. Maguire, David Lafont, Selina A. Pearson, Amy S. Gates, Mark Sanderson, Carl ShannonMaksymilian T. Sumowski, Robbie S.B. McLaren-Jones, Agnieszka Swiatkowska, Christopher M. Isherwood, Emma L. Cambridge, Heather M. Wilson, Susana S. Caetano, Anna Karin B. Maguire, Antonella Galli, Anneliese O. Speak, Joshua Dench, Elizabeth Tuck, Jeanne Estabel, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Icoresi Mazzeo, Yvette Hooks, Fiona Kussy, Mark Griffiths, David Gannon, Brendan Doe, Katharina Boroviak, Hannah Wardle-Jones, Nicola Griggs, Joanna Bottomley, Ed Ryder, Diane Gleeson, Renato Borgatti, Sanger Mouse Genetics Project

Research output: Contribution to journalArticlepeer-review


The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.

Original languageEnglish
Pages (from-to)E9308-E9317
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
Publication statusPublished - Oct 31 2017


  • Autophagy
  • Corpus callosum agenesis
  • Microcephaly
  • Neurogenesis
  • WD40-repeat proteins

ASJC Scopus subject areas

  • General


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