title: Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis.
abstract: Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor β-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a-Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a-Ror-Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hsin-Yi Henry
authors.initials: HY
authors.lastname: Ho
authors.forename: Michael W
authors.initials: MW
authors.lastname: Susman
authors.forename: Jay B
authors.initials: JB
authors.lastname: Bikoff
authors.forename: Yun Kyoung
authors.initials: YK
authors.lastname: Ryu
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Jonas
authors.forename: Linda
authors.initials: L
authors.lastname: Hu
authors.forename: Rejji
authors.initials: R
authors.lastname: Kuruvilla
authors.forename: Michael Eldon
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D000072261:Dishevelled Proteins; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000254:growth & development; D051153:Wnt Proteins / Q000172:deficiency / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477011:Ror1 protein, mouse; C477010:Ror2 protein, mouse