Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre-chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS.
Department of Cell Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Bing
B
Wang
Tanvi
T
Sinha
Kai
K
Jiao
Rosa
R
Serra
Jianbo
J
Wang
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D016764:Cell Polarity / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D018628:Gene Dosage; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D018878:Limb Buds / Q000002:abnormalities; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019767:Maxillofacial Abnormalities / Q000196:embryology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D041641:Musculoskeletal Development / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013131:Spine / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D036341:Intercellular Signaling Peptides and Proteins; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse