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  Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation.

Villavicencio-Lorini, P., Kuss, P., Friedrich, J., Haupt, J., Farooq, M., Turkmen, S., et al. (2010). Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation. Journal of Clinical Investigation, 120(6), 1994-2004. doi:10.1172/JCI41554 41554.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7AE8-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-7AE9-3
Genre: Journal Article
Alternative Title : J Clin Invest

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 Creators:
Villavicencio-Lorini, P.1, Author              
Kuss, P.1, Author              
Friedrich, J.2, Author
Haupt, J.2, Author
Farooq, M., Author
Turkmen, S.3, Author              
Duboule, D., Author
Hecht, J.1, Author              
Mundlos, S.1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Max Planck Society, ou_persistent13              
3Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              

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Free keywords: Alleles; Animals; Bone and Bones/*metabolism; Cartilage/*metabolism; Extremities; Mice, Knockout; Peptides; Signal Transduction/genetics; Transcription Factors/biosynthesis/*genetics/*metabolism
 Abstract: The molecular mechanisms that govern bone and joint formation are complex, involving an integrated network of signaling pathways and gene regulators. We investigated the role of Hox genes, which are known to specify individual segments of the skeleton, in the formation of autopod limb bones (i.e., the hands and feet) using the mouse mutant synpolydactyly homolog (spdh), which encodes a polyalanine expansion in Hoxd13. We found that no cortical bone was formed in the autopod in spdh/spdh mice; instead, these bones underwent trabecular ossification after birth. Spdh/spdh metacarpals acquired an ovoid shape and developed ectopic joints, indicating a loss of long bone characteristics and thus a transformation of metacarpals into carpal bones. The perichondrium of spdh/spdh mice showed abnormal morphology and decreased expression of Runt-related transcription factor 2 (Runx2), which was identified as a direct Hoxd13 transcriptional target. Hoxd11-/-Hoxd12-/-Hoxd13-/- triple-knockout mice and Hoxd13-/-Hoxa13+/- mice exhibited similar but less severe defects, suggesting that these Hox genes have similar and complementary functions and that the spdh allele acts as a dominant negative. This effect was shown to be due to sequestration of other polyalanine-containing transcription factors by the mutant Hoxd13 in the cytoplasm, leading to their degradation. These data indicate that Hox genes not only regulate patterning but also directly influence bone formation and the ossification pattern of bones, in part via Runx2.

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Language(s): eng - English
 Dates: 2010-06-01
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
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Title: Journal of Clinical Investigation
  Alternative Title : J Clin Invest
Source Genre: Journal
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Pages: - Volume / Issue: 120 (6) Sequence Number: - Start / End Page: 1994 - 2004 Identifier: ISSN: 0021-9738