Dataset Information

Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis.

ABSTRACT: Serum starvation stimulates cilia growth in cultured cells, yet serum factors associated with ciliogenesis are unknown. Previously, we showed that starvation induces rapid Rab11-dependent vesicular trafficking of Rabin8, a Rab8 guanine-nucleotide exchange factor (GEF), to the mother centriole, leading to Rab8 activation and cilium growth. Here, we demonstrate that through the LPA receptor 1 (LPAR1), serum lysophosphatidic acid (LPA) inhibits Rab11a-Rabin8 interaction and ciliogenesis. LPA/LPAR1 regulates ciliogenesis initiation via downstream PI3K/Akt activation, independent of effects on cell cycle. Akt stabilizes Rab11a binding to its effector, WDR44, and a WDR44-pAkt-phosphomimetic mutant blocks ciliogenesis. WDR44 depletion promotes Rabin8 preciliary trafficking and ciliogenesis-initiating events at the mother centriole. Our work suggests disruption of Akt signaling causes a switch from Rab11-WDR44 to the ciliogenic Rab11-FIP3-Rabin8 complex. Finally, we demonstrate that Akt regulates downstream ciliogenesis processes associated with Rab8-dependent cilia growth. Together, this study uncovers a mechanism whereby serum mitogen signaling regulates Rabin8 preciliary trafficking and ciliogenesis initiation.

SUBMITTER: Walia V

PROVIDER: S-EPMC7457226 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis.

Walia Vijay V Cuenca Adrian A Vetter Melanie M Insinna Christine C Perera Sumeth S Lu Quanlong Q Ritt Daniel A DA Semler Elizabeth E Specht Suzanne S Stauffer Jimmy J Morrison Deborah K DK Lorentzen Esben E Westlake Christopher J CJ

Developmental cell 20190613 2

Serum starvation stimulates cilia growth in cultured cells, yet serum factors associated with ciliogenesis are unknown. Previously, we showed that starvation induces rapid Rab11-dependent vesicular trafficking of Rabin8, a Rab8 guanine-nucleotide exchange factor (GEF), to the mother centriole, leading to Rab8 activation and cilium growth. Here, we demonstrate that through the LPA receptor 1 (LPAR1), serum lysophosphatidic acid (LPA) inhibits Rab11a-Rabin8 interaction and ciliogenesis. LPA/LPAR1 ...[more]

PMID: 31204173

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Project 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.

Dataset Information

Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis.

Publications

Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis.

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