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Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors
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 develo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10241521/ https://www.ncbi.nlm.nih.gov/pubmed/37272619 http://dx.doi.org/10.7554/eLife.81716 |
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author | Dell'Amico, Claudia Angulo Salavarria, Marilyn M Takeo, Yutaka Saotome, Ichiko Dell'Anno, Maria Teresa Galimberti, Maura Pellegrino, Enrica Cattaneo, Elena Louvi, Angeliki Onorati, Marco |
author_facet | Dell'Amico, Claudia Angulo Salavarria, Marilyn M Takeo, Yutaka Saotome, Ichiko Dell'Anno, Maria Teresa Galimberti, Maura Pellegrino, Enrica Cattaneo, Elena Louvi, Angeliki Onorati, Marco |
author_sort | Dell'Amico, Claudia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10241521 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-102415212023-06-06 Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors Dell'Amico, Claudia Angulo Salavarria, Marilyn M Takeo, Yutaka Saotome, Ichiko Dell'Anno, Maria Teresa Galimberti, Maura Pellegrino, Enrica Cattaneo, Elena Louvi, Angeliki Onorati, Marco eLife Stem Cells and Regenerative Medicine 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. eLife Sciences Publications, Ltd 2023-06-05 /pmc/articles/PMC10241521/ /pubmed/37272619 http://dx.doi.org/10.7554/eLife.81716 Text en © 2023, Dell'Amico et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Stem Cells and Regenerative Medicine Dell'Amico, Claudia Angulo Salavarria, Marilyn M Takeo, Yutaka Saotome, Ichiko Dell'Anno, Maria Teresa Galimberti, Maura Pellegrino, Enrica Cattaneo, Elena Louvi, Angeliki Onorati, Marco Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title | Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title_full | Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title_fullStr | Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title_full_unstemmed | Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title_short | Microcephaly-associated protein WDR62 shuttles from the Golgi apparatus to the spindle poles in human neural progenitors |
title_sort | microcephaly-associated protein wdr62 shuttles from the golgi apparatus to the spindle poles in human neural progenitors |
topic | Stem Cells and Regenerative Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10241521/ https://www.ncbi.nlm.nih.gov/pubmed/37272619 http://dx.doi.org/10.7554/eLife.81716 |
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