State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, 100101, China.
Cell Death Dis. 2021 Jan 12;12(1):75. doi: 10.1038/s41419-020-03363-3.
Mutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I-V), a group of lethal congenital disorders characterized by short ribs, polydactyly, and a range of extraskeletal phenotypes. However, the underlying mechanism is still unclear. Here, we report that WDR60 is essential for embryonic development and plays a critical role in the multipolar-bipolar transition and migration of newborn neurons during brain development. Mechanically, we found that WDR60 was located at the microtubule-organizing center to control microtubule organization and possibly, the trafficking of cellular components. Importantly, the migration defect caused by Wdr60 knockdown could be rescued by the stable form of α-Tubulin, α-Tubulin (an acetylation-mimicking mutant). These findings identified a non-cilia function of WDR60 and provided insight into its biological function, as well as the pathogenesis of WDR60 deficiency associated with SRPS.
WD40 重复结构域 60（WDR60）突变已在短肋多指畸形综合征（SRPS I-V）中被鉴定出来，这是一组致命的先天性疾病，其特征是肋骨短小、多指畸形和一系列骨骼外表型。然而，其潜在的机制仍不清楚。在这里，我们报告 WDR60 对胚胎发育是必需的，并且在大脑发育过程中对新生神经元的多极-两极转变和迁移起着关键作用。从机制上看，我们发现 WDR60 位于微管组织中心以控制微管组织，可能还有细胞成分的运输。重要的是，Wdr60 敲低引起的迁移缺陷可以通过稳定形式的α-微管蛋白（α-Tubulin，一种乙酰化模拟突变体）来挽救。这些发现确定了 WDR60 的非纤毛功能，并深入了解了其生物学功能以及与 SRPS 相关的 WDR60 缺乏症的发病机制。
