標題: Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation
作者: Tsai, Meng-Han
Cheng, Haw-Yuan
Nian, Fang-Shin
Liu, Chen
Chao, Nian-Hsin
Chiang, Kuo-Liang
Chen, Shu-Fang
Tsai, Jin-Wu
生物科技學系
Department of Biological Science and Technology
公開日期: 14-七月-2020
摘要: During brain development, the nucleus of migrating neurons follows the centrosome and translocates into the leading process. Defects in these migratory events, which affect neuronal migration, cause lissencephaly and other neurodevelopmental disorders. However, the mechanism of nuclear translocation remains elusive. Using whole exome sequencing (WES), we identified a novel nonsense BICD2 variant p.(Lys775Ter) (K775X) from a lissencephaly patient. Interestingly, most BICD2 missense variants have been associated with human spinal muscular atrophy (SMA) without obvious brain malformations. By in utero electroporation, we showed that BicD2 knockdown in mouse embryos inhibited neuronal migration. Surprisingly, we observed severe blockage of neuronal migration in cells overexpressing K775X but not in those expressing wild-type BicD2 or SMA-associated missense variants. The centrosome of the mutant was, on average, positioned farther away from the nucleus, indicating a failure in nuclear translocation without affecting the centrosome movement. Furthermore, BicD2 localized at the nuclear envelope (NE) through its interaction with NE protein Nesprin-2. K775X variant disrupted this interaction and further interrupted the NE recruitment of BicD2 and dynein. Remarkably, fusion of BicD2-K775X with NE-localizing domain KASH resumed neuronal migration. Our results underscore impaired nuclear translocation during neuronal migration as an important pathomechanism of lissencephaly.
URI: http://dx.doi.org/10.1186/s40478-020-00971-0
http://hdl.handle.net/11536/155194
ISSN: 2051-5960
DOI: 10.1186/s40478-020-00971-0
期刊: ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume: 8
Issue: 1
起始頁: 0
結束頁: 0
顯示於類別:期刊論文