Institut Curie, PSL Research University, CNRS UMR144, 75005, Paris, France.
Epigenetics and Cell Fate (EDC) department, UMR7216, Centre National de la Recherche Scientifique (CNRS), Université de Paris, F-75013, Paris, France.
Nat Commun. 2022 Jan 10;13(1):16. doi: 10.1038/s41467-021-27705-7.
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.
原发性小头畸形和巨脑畸形是由脑体积缩小和增大分别定义的严重脑畸形。这两种病理是否来自分子水平上的相关改变尚不清楚。小头畸形主要与中心体缺陷有关，导致细胞死亡。在这里，我们研究了 WDR81 功能丧失的后果，WDR81 功能丧失会导致患者出现严重的小头畸形。我们表明，WDR81 调节 EGFR 的内体运输，功能丧失会导致 MAP 激酶途径激活减少。WDR81 敲除的小鼠放射状胶质祖细胞增殖率降低，随后导致脑体积减小。体内表达 Cyclin D2 引起的巨脑畸形突变形式可挽救这些增殖缺陷。我们的结果确定了内体机制作为增殖率和大脑生长的重要调节剂，表明小头畸形和巨脑畸形可通过对放射状胶质祖细胞增殖率的相反影响而引起。
