2. Academic Validation
  3. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

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

  • Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9308-E9317. doi: 10.1073/pnas.1713625114.
Meghna Kannan 1 2 3 4 5,  Efil Bayam 1 2 3 4,  Christel Wagner 1 2 3 4,  Bruno Rinaldi 6,  Perrine F Kretz 1 2 3 4,  Peggy Tilly 1 2 3 4,  Marna Roos 7,  Lara McGillewie 8,  Séverine Bär 6,  Shilpi Minocha 5,  Claire Chevalier 1 2 3 4,  Chrystelle Po 9,  Sanger Mouse Genetics Project,  Jamel Chelly 1 2 3 4,  Jean-Louis Mandel 1 2 3 4,  Renato Borgatti 10,  Amélie Piton 1 2 3 4,  Craig Kinnear 8,  Ben Loos 7,  David J Adams 11,  Yann Hérault 1 2 3 4,  Stephan C Collins 1 2 3 4 12,  Sylvie Friant 6,  Juliette D Godin 1 2 3 4,  Binnaz Yalcin 13 2 3 4
Affiliations

Affiliations

  • 1 Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
  • 2 Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.
  • 3 Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France.
  • 4 Université de Strasbourg, 67404 Illkirch, France.
  • 5 Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
  • 6 Génétique Moléculaire Génomique Microbiologie, UMR7156, Université de Strasbourg, CNRS, 67000 Strasbourg, France.
  • 7 Department of Physiological Sciences, University of Stellenbosch, 7600 Stellenbosch, South Africa.
  • 8 South African Medical Research Council Centre for Tuberculosis Research, Department of Biomedical Sciences, University of Stellenbosch, 7505 Tygerberg, South Africa.
  • 9 ICube, UMR 7357, Fédération de Médecine Translationnelle, University of Strasbourg, 67085 Strasbourg, France.
  • 10 Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy.
  • 11 Wellcome Trust Sanger Institute, Hinxton, CB10 1SA Cambridge, United Kingdom.
  • 12 Centre des Sciences du Goût et de l'Alimentation, Université de Bourgogne-Franche Comté, 21000 Dijon, France.
  • 13 Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Binnaz.Yalcin@igbmc.fr.
PMID: 29078390 DOI: 10.1073/pnas.1713625114
Abstract

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.

Keywords

WD40-repeat proteins; autophagy; corpus callosum agenesis; microcephaly; neurogenesis.

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