Article: article from journal or magazin.
WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy.
Proceedings of the National Academy of Sciences of the United States of America
Sanger Mouse Genetics Project
Vancollie V.E., Anthony LFE, Maguire S.A., Lafont D., Pearson S.A., Gates A.S., Sanderson M., Shannon C., Sumowski M.T., McLaren-Jones RSB, Swiatkowska A., Isherwood C.M., Cambridge E.L., Wilson H.M., Caetano S.S., Maguire AKB, Galli A., Speak A.O., Dench J., Tuck E., Estabel J., Green A., Tudor C., Siragher E., Dabrowska M., Mazzeo C.I., Hooks Y., Kussy F., Griffiths M., Gannon D., Doe B., Boroviak K., Wardle-Jones H., Griggs N., Bottomley J., Ryder E., Gleeson D., White J.K., Ramirez-Solis R., Lelliott C.J.
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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 ( <i>Atg16l1</i> , <i>Coro1c</i> , <i>Dmxl2</i> , and <i>Herc1</i> ), thinner ( <i>Kif21b</i> and <i>Wdr89</i> ), or absent corpus callosum ( <i>Wdr47</i> ), 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 <i>Wdr47</i> 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.
Animals, Autophagy/physiology, Brain/growth & development, Brain/metabolism, Cell Movement/physiology, Cell Proliferation/physiology, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Microfilament Proteins/metabolism, Microtubule-Associated Proteins/metabolism, Microtubules/metabolism, Microtubules/physiology, Neurogenesis/physiology, Neurons/metabolism, Neurons/physiology, Phenotype, Stem Cells/metabolism, Stem Cells/physiology, WD40 Repeats/physiology, WD40-repeat proteins, autophagy, corpus callosum agenesis, microcephaly, neurogenesis
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