Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in tran...

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Autores principales:	Behnam Rashidieh, Belal Shohayeb, Amanda Louise Bain, Patrick R J Fortuna, Debottam Sinha, Andrew Burgess, Richard Mills, Rachael C Adams, J Alejandro Lopez, Peter Blumbergs, John Finnie, Murugan Kalimutho, Michael Piper, James Edward Hudson, Dominic C H Ng, Kum Kum Khanna
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/f8a4d81f071f4f57a27dc411b7082140
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spelling	oai:doaj.org-article:f8a4d81f071f4f57a27dc411b70821402021-12-02T20:03:29ZCep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.1553-73901553-740410.1371/journal.pgen.1009334https://doaj.org/article/f8a4d81f071f4f57a27dc411b70821402021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009334https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3β/β-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3β. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.Behnam RashidiehBelal ShohayebAmanda Louise BainPatrick R J FortunaDebottam SinhaAndrew BurgessRichard MillsRachael C AdamsJ Alejandro LopezPeter BlumbergsJohn FinnieMurugan KalimuthoMichael PiperJames Edward HudsonDominic C H NgKum Kum KhannaPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 10, p e1009334 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Behnam Rashidieh Belal Shohayeb Amanda Louise Bain Patrick R J Fortuna Debottam Sinha Andrew Burgess Richard Mills Rachael C Adams J Alejandro Lopez Peter Blumbergs John Finnie Murugan Kalimutho Michael Piper James Edward Hudson Dominic C H Ng Kum Kum Khanna Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
description	Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3β/β-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3β. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.
format	article
author	Behnam Rashidieh Belal Shohayeb Amanda Louise Bain Patrick R J Fortuna Debottam Sinha Andrew Burgess Richard Mills Rachael C Adams J Alejandro Lopez Peter Blumbergs John Finnie Murugan Kalimutho Michael Piper James Edward Hudson Dominic C H Ng Kum Kum Khanna
author_facet	Behnam Rashidieh Belal Shohayeb Amanda Louise Bain Patrick R J Fortuna Debottam Sinha Andrew Burgess Richard Mills Rachael C Adams J Alejandro Lopez Peter Blumbergs John Finnie Murugan Kalimutho Michael Piper James Edward Hudson Dominic C H Ng Kum Kum Khanna
author_sort	Behnam Rashidieh
title	Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
title_short	Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
title_full	Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
title_fullStr	Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
title_full_unstemmed	Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.
title_sort	cep55 regulation of pi3k/akt signaling is required for neocortical development and ciliogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/f8a4d81f071f4f57a27dc411b7082140
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Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.

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