title: The PDZ domain protein Mcc is a novel effector of non-canonical Wnt signaling during convergence and extension in zebrafish.
abstract: During vertebrate gastrulation, a complex set of mass cellular rearrangements shapes the embryonic body plan and appropriately positions the organ primordia. In zebrafish and Xenopus, convergence and extension (CE) movements simultaneously narrow the body axis mediolaterally and elongate it from head to tail. This process is governed by polarized cell behaviors that are coordinated by components of the non-canonical, β-catenin-independent Wnt signaling pathway, including Wnt5b and the transmembrane planar cell polarity (PCP) protein Vangl2. However, the intracellular events downstream of Wnt/PCP signals are not fully understood. Here, we show that zebrafish mutated in colorectal cancer (mcc), which encodes an evolutionarily conserved PDZ domain-containing putative tumor suppressor, is required for Wnt5b/Vangl2 signaling during gastrulation. Knockdown of mcc results in CE phenotypes similar to loss of vangl2 and wnt5b, whereas overexpression of mcc robustly rescues the depletion of wnt5b, vangl2 and the Wnt5b tyrosine kinase receptor ror2. Biochemical experiments establish a direct physical interaction between Mcc and the Vangl2 cytoplasmic tail. Lastly, CE defects in mcc morphants are suppressed by downstream activation of RhoA and JNK. Taken together, our results identify Mcc as a novel intracellular effector of non-canonical Wnt5b/Vangl2/Ror2 signaling during vertebrate gastrulation.
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Teddy
authors.initials: T
authors.lastname: Young
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Yogavalli
authors.initials: Y
authors.lastname: Poobalan
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Ee Kim
authors.initials: EK
authors.lastname: Tan
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543.
authors.forename: Shijie
authors.initials: S
authors.lastname: Tao
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Sheena
authors.initials: S
authors.lastname: Ong
authors.affiliation: Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, GZMB, University of Göttingen, Göttingen 37077, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wehner
authors.affiliation: Department of Biology, Molecular Embryology, Philipps-University Marburg, Marburg 35043, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Schwenty-Lara
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Chin Yan
authors.initials: CY
authors.lastname: Lim
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Akila
authors.initials: A
authors.lastname: Sadasivam
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lovatt
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Siew Tein
authors.initials: ST
authors.lastname: Wang
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Ali
authors.affiliation: Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, GZMB, University of Göttingen, Göttingen 37077, Germany Department of Biology, Molecular Embryology, Philipps-University Marburg, Marburg 35043, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Borchers
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543 Division of Biomedical Cell Biology, B040, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Karuna
authors.initials: K
authors.lastname: Sampath
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06 Immunos, Singapore 138648 ray.dunn@imb.a-star.edu.sg.
authors.forename: N Ray
authors.initials: NR
authors.lastname: Dunn
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016764:Cell Polarity / Q000502:physiology; D054262:Gastrulation / Q000502:physiology*; D017431:Genes, MCC / Q000235:genetics*; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008156:Luciferases; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D054731:PDZ Domains / Q000235:genetics; D016133:Polymerase Chain Reaction; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000071818:Wnt-5a Protein; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C480282:Wnt5a protein, zebrafish; D029961:Zebrafish Proteins; C491759:vangl2 protein, zebrafish; D008156:Luciferases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors
keywords: Actin cytoskeleton; Convergence and extension; Mutated in colorectal cancer (Mcc); Non-canonical Wnt signaling; Zebrafish