title: Long bone development requires a threshold of Hox function.
abstract: The Hoxd(Del(11-13)) mutant is one of the animal models for human synpolydactyly, characterized by short and syndactylous digits. Here we have characterized in detail the cartilage and bone defects in these mutants. We report two distinct phenotypes: (i) a delay and change in pattern of chondrocyte maturation of metacarpals/metatarsals and (ii) formation of a poor and not centrally positioned primary ossification center in the proximal-intermediate phalanx. In the metacarpals of Hoxd(Del(11-13)) mutants, ossification occurs postnataly, in the absence of significant Ihh expression and without the establishment of growth plates, following patterns similar to those of short bones. The strong downregulation in Ihh expression is associated with a corresponding increase of the repressor form of Gli3. To evaluate the contribution of this alteration to the phenotype, we generated double Hoxd(Del(11-13));Gli3 homozygous mutants. Intriguingly, these double mutants showed a complete rescue of the phenotype in metatarsals but only partial phenotypic rescue in metacarpals. Our results support Hox genes being required in a dose-dependent manner for long bone cartilage maturation and suggest that and excess of Gli3R mediates a significant part of the Hoxd(Del(11-13)) chondrogenic phenotype.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN., 39011 Santander, Spain.
authors.forename: Ma Carmen
authors.initials: MC
authors.lastname: González-Martín
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
authors.forename: Moises
authors.initials: M
authors.lastname: Mallo
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN., 39011 Santander, Spain; Dpto. de Anatomía y Biología Celular, Universidad de Cantabria, 39011 Santander, Spain. Electronic address: rosm@unican.es.
authors.forename: Marian A
authors.initials: MA
authors.lastname: Ros
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001846:Bone Development / Q000235:genetics* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism; D006652:Histological Techniques; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013576:Syndactyly / Q000235:genetics* / Q000473:pathology*; D000074290:Zinc Finger Protein Gli3
chemical_list: D017931:DNA Primers; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; C514061:ihh protein, mouse
keywords: Chondrogenesis; Gli3; Hoxd genes; Ihh; Osteogenesis; Short-bones