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Dev Biol. 2014 Aug 15;392(2):454-65. doi: 10.1016/j.ydbio.2014.06.004. Epub 2014 Jun 12.

Long bone development requires a threshold of Hox function.

Author information

1
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-SODERCAN., 39011 Santander, Spain.
2
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
3
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.

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.

KEYWORDS:

Chondrogenesis; Gli3; Hoxd genes; Ihh; Osteogenesis; Short-bones

PMID:
24930703
DOI:
10.1016/j.ydbio.2014.06.004
[Indexed for MEDLINE]
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