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

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Rashidieh, Behnam
Shohayeb, Belal
Bain, Amanda Louise
Fortuna, Patrick RJ
Sinha, Debottam
Burgess, Andrew
Mills, Richard
Adams, Rachael C
Lopez, J Alejandro
Blumbergs, Peter
Finnie, John
Kalimutho, Murugan
Piper, Michael
Hudson, James Edward
Ng, Dominic CH
Khanna, Kum Kum
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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.

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PLOS Genetics
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© 2021 Rashidieh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Rashidieh, B; Shohayeb, B; Bain, AL; Fortuna, PRJ; Sinha, D; Burgess, A; Mills, R; Adams, RC; Lopez, JA; Blumbergs, P; Finnie, J; Kalimutho, M; Piper, M; Hudson, JE; Ng, DCH; Khanna, KK, Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis, PLOS Genetics, 17 (10), pp. e1009334