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XB-ART-49395
Proc Natl Acad Sci U S A September 9, 2014; 111 (36): 13099-104.

Custos controls β-catenin to regulate head development during vertebrate embryogenesis.

Komiya Y , Mandrekar N , Sato A , Dawid IB , Habas R .


Abstract
Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders. A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of β-catenin, a process that remains incompletely understood. Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelled-interacting protein. Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis. Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer. In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited β-catenin/TCF-dependent transcription. Custos binds to β-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of β-catenin. This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling. The function of Custos is conserved as loss-of-function and gain-of-function studies in zebrafish also demonstrate a role for Custos in anterior head development. Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-β-catenin signal transduction cascade.

PubMed ID: 25157132
PMC ID: PMC4246939
Article link: Proc Natl Acad Sci U S A
Grant support: [+]
Genes referenced: c12orf43 csnk1a1 csnk1g2 dvl1 dvl2 egr2 en2 foxg1 gsc krt8.1 myc ncam1 nodal3.1 nodal3.2 odc1 otx2 pax2 rax rhoa six3 wnt1 wnt3a wnt8a
Morpholinos: c12orf43 MO1


Article Images: [+] show captions
References:
Clevers, 2012, Pubmed [+]


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