Molecular Pathology and Embryology of HOXD Related Limb Malformations

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Hox genes are master genes of development that control patterning and morphogenesis in many parts of the body including the limb. Mutations in Hox genes result in various limb malformations, a prominent example being the poly-Ala expansion in Hoxd13 which causes synpolydactyly (SPD). In this study we will investigate the molecular pathology of HOXD-related limb malformations combining a human genetic approach with developmental genetics using in vivo and in vitro model systems. We will investigate previously identified human HOXD13 missense mutations in chick cell culture systems to identify altered target gene recognition. Based on our previous findings that bone and cartilage formation is severely altered in Hoxd13 mutants we will investigate the role of Hox genes in chondrocyte and osteoblast differentiation. We hypothesize that Hoxd-regulated Wnt genes are involved in the polarization of chondrocytes and will investigate this using in situ hybridization screens, gene regulation assays and metatarsal organ culture. Based on our expression screen we aim at identifying a transcriptional network around the Hoxd-genes that controls bone formation. The dominant negative character of the Hoxd13 poly-Ala mutations will be investigated.