title: Regulation of cell polarity in the cartilage growth plate and perichondrium of metacarpal elements by HOXD13 and WNT5A.
abstract: The morphology of bones is genetically determined, but the molecular mechanisms that control shape, size and the overall gestalt of bones remain unclear. We previously showed that metacarpals in the synpolydactyly homolog (spdh) mouse, which carries a mutation in Hoxd13 similar to the human condition synpolydactyly (SPD), were transformed to carpal-like bones with cuboid shape that lack cortical bone and a perichondrium and are surrounded by a joint surface. Here we provide evidence that spdh metacarpal growth plates have a defect in cell polarization with a random instead of linear orientation. In parallel prospective perichondral cells failed to adopt the characteristic flattened cell shape. We observed a similar cell polarity defect in metacarpals of Wnt5a(-/-) mice. Wnt5a and the closely related Wnt5b were downregulated in spdh handplates, and HOXD13 induced expression of both genes in vitro. Concomitant we observed mislocalization of core planar cell polarity (PCP) components DVL2 and PRICKLE1 in spdh metacarpals indicating a defect in the WNT/PCP pathway. Conversely the WNT/β-CATENIN pathway, a hallmark of joint cells lining carpal bones, was upregulated in the perichondral region. Finally, providing spdh limb explant cultures with cells expressing either HOXD13 or WNT5A led to a non-cell autonomous partial rescue of cell polarity the perichondral region and restored the expression of perichondral markers. This study provides a so far unrecognized link between HOX proteins and cell polarity in the perichondrium and the growth plate, a failure of which leads to transformation of metacarpals to carpal-like structures.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité University Medicine, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Kuss
authors.forename: Katerina
authors.initials: K
authors.lastname: Kraft
authors.forename: Jürgen
authors.initials: J
authors.lastname: Stumm
authors.forename: Daniel
authors.initials: D
authors.lastname: Ibrahim
authors.forename: Pedro
authors.initials: P
authors.lastname: Vallecillo-Garcia
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002356:Cartilage / Q000196:embryology* / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D000072261:Dishevelled Proteins; D006132:Growth Plate / Q000196:embryology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism; D050279:Metacarpal Bones / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D017478:Receptors, Phencyclidine / Q000378:metabolism; D013576:Syndactyly / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D060588:LIM Domain Proteins; D010750:Phosphoproteins; C524253:Prickle1 protein, mouse; D017478:Receptors, Phencyclidine; D014157:Transcription Factors; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin
keywords: Cartilage; Cell polarity; Growth plate; Hoxd13; Perichondrium; Wnt5a