Proc Natl Acad Sci U S A.: auth.: group Reymond & co-auth.: group Herr

Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9308-E9317. doi: 10.1073/pnas.1713625114. Epub 2017 Oct 12.

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

Kannan M1,2,3,4,5Bayam E1,2,3,4Wagner C1,2,3,4Rinaldi B6Kretz PF1,2,3,4Tilly P1,2,3,4Roos M7McGillewie L8Bär S6Minocha S5Chevalier C1,2,3,4Po C9Sanger Mouse Genetics ProjectChelly J1,2,3,4Mandel JL1,2,3,4Borgatti R10Piton A1,2,3,4Kinnear C8Loos B7Adams DJ11Hérault Y1,2,3,4Collins SC1,2,3,4,12Friant S6Godin JD1,2,3,4Yalcin B13,2,3,4.


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 (Atg16l1Coro1cDmxl2, 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.


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

PMID: 29078390