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Hox-Genes Regulate Bone Formation

Prof. Mundlos (first supervisor), Prof. Knaus (second supervisor); Max Planck Institute for Molecular Genetics and Freie Universität Berlin

Hox Genes are a family of transcription factors that regulate the bauplan of species as distant as Drosophila and humans. For example, a loss-of-function mutation in the regulatory region of the Drosophila antennapedia gene can result in the development of the second leg pair into ectopic antennae. By contrast, gain-of-function alleles convert antennae into ectopic legs. In humans, mutations in Hox genes result in various limb malformations, such as synpolydactyly (1). Besides their function in controlling overall patterns of development, Hox genes were shown by us to be important for the regulation of stem cell differentiation. In particular, they control the differentiation of progenitor cells into osteoblasts and chondrocytes (2). In addition, they influence the differentiation of growth plate chondrocytes. It is the aim of this project to decipher the regulatory network that governs stem cell differentiation in bone formation and regeneration.
To address this question we will study a number of mouse mutants that are available in the lab (3,4). We will use these mutants to inactivate various combinations of Hox genes in the limb in order to identify and evaluate down stream targets that may be involved in bone formation. In a previous study we were able to identify the transcription factor Runx2 as a major target of Hox regulation. Runx2 is essential for bone formation. In Hoxd13 mutant mice Runx2 is absent from the metacarpal bones in the limbs which, as a consequence, results in the absence of bone in this part of the body. We will investigate how Hox genes regulate Runx2 and will aim at identifying additional targets that are invovled in this process. This will be done by a novel technology involving chromatin immunoprecipitation with following massive parallel sequencing using next generation sequencing technology. This technology (ChIPSeq) allows a genome-wide identification of Hox-target genes. Selected target genes will then be evaluated in our mouse models. In a second part of the project we will investigate the role of Hox genes in bone regeneration. We will conditionally inactivate Hox genes using an inducible promotor in 3 months old mice. These mice will then be used to induce a fracture. Healing of the fracture in knock outs vs. controls will be evaluated with established methods. These experiments will give insights into the reactivation of developmental genes in regeneration.

References
Muragaki Y, Mundlos S, Upton J, Olsen BR. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science. 1996; 272(5261): 548-51.

Kuss P, Villavicencio-Lorini P, Witte F, Seemann P, Hecht J, Mundlos S. A Molecular Pathogenesis for Hoxd13 Associated Polydactyly. J. Clin. Invest. 2008; in press

Albrecht AN, Schwabe GC, Stricker S, Böddrich A, Wanker EE, Mundlos S. The synpolydactyly homolog (spdh) mutation in the mouse -- a defect in patterning and growth of limb cartilage elements. Mech. Dev. 2002; 112(1-2):53-67.

Albrecht AN, Kornak U, Böddrich A, Süring K, Robinson PN, Stiege AC, Lurz R, Stricker S, Wanker EE, Mundlos S. A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. Hum. Mol. Genet. 2004; 15;13(20):2351-9.