ANALYSIS OF THE ROLE PLAYED BY P63 AND DLX GENES IN THE PATHOGENESIS OF SPLIT HAND AND FOOT MALFORMATION-4

The Split Hand/split Foot Malformation (SHFM), also known as ectrodactily, occurs in approximately 1 in 18000 newborns. In almost 40% of the cases, ectrodactyly is associated with other anomalies that generate clinically distinguishable pathologies. Well-known examples of this association are the Ectrodactyly, Ectodermal dysplasia and Cleft lip/palate(EEC) and the Limb Mammary Syndrome (LMS) syndromes. Evidences have been reported in litterature proving the involvement of the DLX5, DLX6, p63, and Dactylyn genes in these syndromes. Interestingly, molecular lesions of the p63 gene, encoding a transcription factor, are also causative of the Ankyloblepharon Ectodermal dysplasia Clefting (AEC), a syndrome characterized by skin alterations without limb defects while the AEC-like Tricho-Dento-Osseous (TDO) syndrome, is due to the functional inactivation of DLX3. The strong similarities among all these conditions indicate that the various genes involved in these diseases could be organized in a common cascade of regulatory events regulating limb and epidermal development. EEC-like limb deformities and developmental malformations were detected in human feti in the 1950s, when pregnant women used the anti-nausea drug Thalidomide. Preliminary experiments, performed by us on Thalidomide-treated mammalian cells and Xenopus embryos, suggest that p63 is a molecular target of Thalidomide during development. In this proposal we intend to i) identify the regulative elements conferring p63-responsiveness to Dlx genes, ii) determine the p63 protein modification induced by Thalidomide iii) Verify how the expression of Dlx and other p63 responsive genes is affected in Thalidomide treated HaCaT cells and Xenopus embryos. We expect our study to shed light on cellular pathways regulating skin and limb development and help to devise strategies for therapies that alleviate symptoms of these hereditary pathologies.