By carrying out this project we have accumulated significant new knowledge on the molecular regulations underlying the EEC and SF syndromes. By combining genetic, histological, cellular and biochemical analyses on mouse models of these disease, we now have uncovered four novel regulations, relevant for these diseases: 1) Pin1 negatively controls p63 stability, and this is prevented by FGF8; 2) the p300 acetylase also controls p63 stability and is controlled by FGF8; 3) Dlx5;Dlx6 control transcription of FGF8 and Wnt5a, which act to define cell polarity, oriented migration and are needed for normal limb development, and 4) p63 regulates Irf6, which in turn back-regulates p63. All this knowledge is now available for translation towards a putative therapeutic approach to restore normal skin, limb and palate development. In fact, we have succeeded in maintaining embryonic tissues in cultures, and we have been able to restore AER function of diseased limbs by the simple addition of FGF8+Wnt5a. This opens the way of using Wnt5a (alone or combined with FGF8) or by transducing the Wnt5a gene (with adenoviral vectors) and hope to restore limb development during embryonic life. Similar work is underway for the palate and the skin, two other organs affected in EEC and Ectodermal Dysplasia in general.