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541210.0 [No comment] 10.03.2011 12:17 Released

ID: 541210.0, MPI für molekulare Genetik / Research Group Development and Disease
Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation.
Authors:Villavicencio-Lorini, P.; Kuss, P.; Friedrich, J.; Haupt, J.; Farooq, M.; Turkmen, S.; Duboule, D.; Hecht, J.; Mundlos, S.
Research Context:This work was supported by a grant from the Deutsche Forschungs­gemeinschaft (DFG) to Stefan Mundlos.
Date of Publication (YYYY-MM-DD):2010-06-01
Title of Journal:Journal of Clinical Investigation
Journal Abbrev.:J Clin Invest
Issue / Number:6
Start Page:1994
End Page:2004
Copyright:© 2010, American Society for Clinical Investigation
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Free Keywords:Alleles;
Bone and Bones/*metabolism;
Cartilage/*metabolism; Extremities;
Mice, Knockout; Peptides;
Signal Transduction/genetics;
Transcription Factors/biosynthesis/*genetics/*metabolism
Comment of the Author/Creator:Address correspondence to: Stefan Mundlos, Institute for Medical Genetics, Charité, Universitätsmedizin Berlin,
Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute for Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany;
2.Human Molecular Genetics Laboratory, National Institute for Biotechnology & Genetic Engineering (NIBGE), Faisalabad, Pakistan;
3.National Research Centre Frontiers in Genetics, Department of Zoology and Animal Biology, University of Geneva, Geneva, Switzerland;
4.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité, Universitätsmedizin Berlin, Berlin, Germany,
Identifiers:ISSN:0021-9738 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/20458143 [ID No:2]
DOI:10.1172/JCI41554 41554 [ID No:3]
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