Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
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
_version_ 1785054002483822592
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
work_keys_str_mv AT dellamicoclaudia microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT angulosalavarriamarilynm microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT takeoyutaka microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT saotomeichiko microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT dellannomariateresa microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT galimbertimaura microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT pellegrinoenrica microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT cattaneoelena microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT louviangeliki microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors
AT onoratimarco microcephalyassociatedproteinwdr62shuttlesfromthegolgiapparatustothespindlepolesinhumanneuralprogenitors