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/ca113dc23d2f42909600bf1b070bc7e6
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spelling	oai:doaj.org-article:ca113dc23d2f42909600bf1b070bc7e62021-11-18T06:15:45ZCep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis1553-73901553-7404https://doaj.org/article/ca113dc23d2f42909600bf1b070bc7e62021-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577787/?tool=EBIhttps://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. Author summary Despite extensive investigation on the roles of CEP55 in tumorigenesis, its physiological role during development has remained largely uncharacterized. Recently, homozygous CEP55 mutations have been linked to two lethal fetal syndromes, MKS-like Syndrome and MARCH, demonstrating the importance of CEP55 in embryogenesis and neural development. These syndromes exhibit multiple severe clinical manifestations that lead to perinatal lethality. However, the exact molecular mechanism underlying complex Cep55-deficient developmental phenotypes remain elusive. To address this question, we have generated a Cep55-/- (KO) mouse model and to bridge the gap between the mouse model and human disease, we have used brain organoids generated from pluripotent stem cells as a promising approach to investigate the mechanism of Cep55-associated neurodevelopment phenotype. Our detailed mechanistic studies suggest that Cep55 regulates neural development through the Akt-downstream effector, Gsk3β, and its mediators β-Catenin and Myc, which are known regulators of neural proliferation and differentiation. Additionally, we discovered a critical role for Cep55 in regulating cilia formation. Together, these results illustrate an important role of Cep55 in regulating neurogenesis and ciliogenesis via regulation of the Akt pathway.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 (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. Author summary Despite extensive investigation on the roles of CEP55 in tumorigenesis, its physiological role during development has remained largely uncharacterized. Recently, homozygous CEP55 mutations have been linked to two lethal fetal syndromes, MKS-like Syndrome and MARCH, demonstrating the importance of CEP55 in embryogenesis and neural development. These syndromes exhibit multiple severe clinical manifestations that lead to perinatal lethality. However, the exact molecular mechanism underlying complex Cep55-deficient developmental phenotypes remain elusive. To address this question, we have generated a Cep55-/- (KO) mouse model and to bridge the gap between the mouse model and human disease, we have used brain organoids generated from pluripotent stem cells as a promising approach to investigate the mechanism of Cep55-associated neurodevelopment phenotype. Our detailed mechanistic studies suggest that Cep55 regulates neural development through the Akt-downstream effector, Gsk3β, and its mediators β-Catenin and Myc, which are known regulators of neural proliferation and differentiation. Additionally, we discovered a critical role for Cep55 in regulating cilia formation. Together, these results illustrate an important role of Cep55 in regulating neurogenesis and ciliogenesis via regulation of the Akt pathway.
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/ca113dc23d2f42909600bf1b070bc7e6
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Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis

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