Institute of Biological Chemistry, Academia Sinica, Taipei, 115, Taiwan.
Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan.
Cell Death Dis. 2023 Jan 21;14(1):52. doi: 10.1038/s41419-022-05442-z.
Patients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes. However, the underlying mechanisms remain unexplored. Here, we identify a crucial role of Wdr4 in cerebellar development. Wdr4 deficiency in granule neuron progenitors (GNPs) not only reduces foliation and the sizes of external and internal granular layers but also compromises Purkinje neuron organization and the size of the molecular layer, leading to locomotion defects. Mechanistically, Wdr4 supports the proliferation of GNPs by preventing their cell cycle exit. This effect is mediated by Wdr4-induced ubiquitination and degradation of Arhgap17, thereby activating Rac1 to facilitate cell cycle progression. Disease-associated Wdr4 variants, however, cannot provide GNP cell cycle maintenance. Our study identifies Wdr4 as a previously unappreciated participant in cerebellar development and locomotion, providing potential insights into treatment strategies for diseases with WDR4 mutations, such as primordial dwarfism and Galloway-Mowat syndrome.
携带 CUL4 E3 连接酶复合物底物衔接子 WDR4 突变的患者会出现小脑萎缩和步态异常表型，但潜在的发病机制仍不清楚。在这里，我们发现了 Wdr4 在小脑发育中的关键作用。颗粒神经元前体细胞（GNPs）中 Wdr4 的缺失不仅减少了小脑叶片的形成和外颗粒层及内颗粒层的大小，还损害了浦肯野神经元的组织和分子层的大小，导致运动缺陷。从机制上讲，Wdr4 通过阻止其细胞周期退出来支持 GNPs 的增殖。这种效应是由 Wdr4 诱导的 Arhgap17 的泛素化和降解介导的，从而激活 Rac1 促进细胞周期进程。然而，与疾病相关的 Wdr4 变体不能为 GNPs 的细胞周期维持提供支持。我们的研究确定了 Wdr4 是小脑发育和运动的一个以前未被认识的参与者，为治疗携带 WDR4 突变的疾病（如原始侏儒症和 Galloway-Mowat 综合征）提供了潜在的治疗策略。
