title: Custos controls β-catenin to regulate head development during vertebrate embryogenesis.
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.
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Komiya
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122;
authors.forename: Noopur
authors.initials: N
authors.lastname: Mandrekar
authors.affiliation: Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.affiliation: Section on Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD 20892-2790 habas@temple.edu idawid@mail.nih.gov.
authors.forename: Igor B
authors.initials: IB
authors.lastname: Dawid
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122; habas@temple.edu idawid@mail.nih.gov.
authors.forename: Raymond
authors.initials: R
authors.lastname: Habas
mesh_terms: D000818:Animals; D019521:Body Patterning; D002467:Cell Nucleus / Q000378:metabolism; D047108:Embryonic Development; D057809:HEK293 Cells; D006257:Head / Q000196:embryology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D014714:Vertebrates / Q000196:embryology* / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C000596881:C12orf43 protein, Xenopus; D018398:Homeodomain Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C000596880:zgc:162025 protein, zebrafish