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Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors

Authors :
Claudia Dell'Amico
Marilyn M Angulo Salavarria
Yutaka Takeo
Ichiko Saotome
Maria Teresa Dell'Anno
Maura Galimberti
Enrica Pellegrino
Elena Cattaneo
Angeliki Louvi
Marco Onorati
Source :
eLife, Vol 12 (2023)
Publication Year :
2023
Publisher :
eLife Sciences Publications Ltd, 2023.

Abstract

WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions. Recessive mutations in WDR62 cause structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated WDR62 function in corticogenesis through the analysis of a C-terminal truncating mutation (D955AfsX112). Using induced Pluripotent Stem Cells (iPSCs) obtained from a patient and his unaffected parent, as well as isogenic corrected lines, we generated 2D and 3D models of human neurodevelopment, including neuroepithelial stem cells, cerebro-cortical progenitors, terminally differentiated neurons, and cerebral organoids. We report that WDR62 localizes to the Golgi apparatus during interphase in cultured cells and human fetal brain tissue, and translocates to the mitotic spindle poles in a microtubule-dependent manner. Moreover, we demonstrate that WDR62 dysfunction impairs mitotic progression and results in alterations of the neurogenic trajectories of iPSC neuroderivatives. In summary, impairment of WDR62 localization and function results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in the etiology of MCPH.

Details

Language :
English
ISSN :
2050084X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.1d4841c517794d1fae7c77b292a1a852
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.81716