Abstract
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.
Highlights
Centrosomal protein 55 kDa (CEP55) is a crucial regulator of cytokinesis, the final stage of mitotic cell division [1]
Homozygous CEP55 mutations have been linked to two lethal fetal syndromes, Meckel-Gruber syndrome (MKS)-like Syndrome and MARCH, demonstrating the importance of CEP55 in embryogenesis and neural
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
Summary
Centrosomal protein 55 kDa (CEP55) is a crucial regulator of cytokinesis, the final stage of mitotic cell division [1]. Germline mutations of CEP55 in humans have been described in two lethal CEP55-associated syndromes, Meckel-Gruber syndrome (MKS)-like Syndrome [4,5] and MARCH (Multinucleated neurons, Anhydramnios, Renal dysplasia, cerebral hypoplasia, and Hydranencephaly) [6]. These syndromes exhibit severe clinical manifestations, including several congenital malformations, that lead to perinatal lethality. We have generated a Cep55-/- mouse model and cerebral organoids from pluripotent stem cells with or without depletion of CEP55 to investigate the mechanism of CEP55associated neurodevelopment phenotype
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