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Microcephaly-causing WDR81 mutation alters endosomal trafficking of EGFR and leads to reduced progenitor cell proliferation

Abstract : Neocortex development is highly regulated and mutations in genes involved in this process may lead to genetic diseases. Microlissencephaly is a congenital and poorly understood brain malformation characterized by the presence of both microcephaly (small brain) and lissencephaly (smooth brain). Our collaborators recently identified compound heterozygous mutations causing this pathology in the human WD repeat domain 81 (WDR81) gene. WDR81 is a poorly characterized protein involved in endosomal maturation through Pi3K regulation. The goal of my PhD project is to characterize the function of WDR81 in the developing brain, and identify how mutations in this gene may lead to pathological brain development.Using CRISPR/Cas9, I have generated a WDR81 knock-out mouse, which shows strong neuronal migration defects and microcephaly, mimicking the human phenotype. I demonstrated that the reduced brain size was not due to increased apoptosis or altered cell fate, but to reduced neural stem cell proliferation. I also observe this phenotype in patient-derived fibroblasts, altogether suggesting altered processing of proliferative signals. Fluorescent EGF uptake assay reveals a strong intracellular accumulation of EGF in early phases endosomes that fails to be processed and cleared giving as well defects in the activation of the receptor itself. My results indicate that mutant cells indeed poorly respond to EGF stimulation.I then investigated the exciting possibility that reduced brain growth (microcephaly) and increased brain growth (megalencephaly) may represent two sides of the same coin. Because my data point to opposite effects on similar pathways, I overexpressed megalencephaly-causing mutated factors in WDR81 KO brains, and tested whether they were able to rescue the microcephaly-causing proliferation defects. My result show that indeed a megalencephaly-causing mutation can overcome the effect of a microcephaly-causing mutation on the proliferation of radial glial progenitors. These two pathologies can therefore arise from a highly related cause: an imbalance in cell cycle regulation leading either to reduced brain growth or to brain overgrowth.
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Submitted on : Tuesday, January 4, 2022 - 2:19:38 PM
Last modification on : Sunday, June 26, 2022 - 3:30:36 AM


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Jacopo Amerigo Carpentieri. Microcephaly-causing WDR81 mutation alters endosomal trafficking of EGFR and leads to reduced progenitor cell proliferation. Cellular Biology. Université Paris sciences et lettres, 2020. English. ⟨NNT : 2020UPSLT004⟩. ⟨tel-03510180⟩



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