Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

Jacopo A. Carpentieri, Amandine Cicco, Marusa Lampic, David Andreau, Laurence Maestro, Fatima El Marjou, Laure Coquand, Nadia Bahi-Buisson, Jean-Baptiste Brault and Alexandre D. Baffet ()
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Jacopo A. Carpentieri: Institut Curie, PSL Research University, CNRS UMR144
Amandine Cicco: Institut Curie, PSL Research University, CNRS UMR144
Marusa Lampic: Institut Curie, PSL Research University, CNRS UMR144
David Andreau: Institut Curie, PSL Research University, CNRS UMR144
Laurence Maestro: Université de Paris
Fatima El Marjou: Institut Curie, PSL Research University, CNRS UMR144
Laure Coquand: Institut Curie, PSL Research University, CNRS UMR144
Nadia Bahi-Buisson: INSERM U1163, Institut Imagine, Necker Hospital
Jean-Baptiste Brault: Institut Curie, PSL Research University, CNRS UMR144
Alexandre D. Baffet: Institut Curie, PSL Research University, CNRS UMR144

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors.

Date: 2022
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DOI: 10.1038/s41467-021-27705-7

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