Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Tsai, M.-H.; Cheng, Haw-Yuan; Nian, Fang-Shin; Liu, C.; Chao, N.-H.; Chiang, K.-L.; Chen, S.-F.; Tsai, J.-W.

doi:10.1186/s40478-020-00971-0

Article (Scientific journals)

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Tsai, M.-H.; Cheng, Haw-Yuan; Nian, Fang-Shin et al.

2020 • In Acta Neuropathologica Communications, 8 (1)

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https://hdl.handle.net/2268/330639

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10.1186/s40478-020-00971-0

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32665036

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Keywords :

Animals; Brain; Cell Movement; Child, Preschool; Codon, Nonsense; Dyneins; Humans; Lissencephaly; Male; Mice; Microtubule-Associated Proteins; Neurogenesis; Neurons; BICD2 protein, human; dynein adenosine triphosphatase; microtubule associated protein; agyria; animal; brain; case report; cell motion; embryology; genetics; human; male; metabolism; mouse; nerve cell; nervous system development; pathology; preschool child; stop codon

Abstract :

[en] 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. © 2020 The Author(s).

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Tsai, M.-H. ^✱; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

Cheng, Haw-Yuan ^✱; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan

Nian, Fang-Shin ^✱; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Institute of Brain Science, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan

Liu, C.; Program in Molecular Medicine, National Yang-Ming University, Academia Sinica, Taipei, Taiwan

Chao, N.-H.; Department of Pediatric, Kuang Tien General Hospital, Taichung, Taiwan

Chiang, K.-L.; Brain Research Center, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan

Chen, S.-F.; Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan

Tsai, J.-W.; Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan

^✱ These authors have contributed equally to this work.

Language :

English

Title :

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

Publication date :

2020

Journal title :

Acta Neuropathologica Communications

eISSN :

2051-5960

Publisher :

BioMed Central

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Peer reviewed :

Peer Reviewed verified by ORBi

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