Molecular characterization of a novel role of p63 in controlling BMP signaling during embryonic skin development

p63, a p53 family member, plays an essential role in epidermal development by regulating its transcriptional program. Here we report a previously uncovered role of p63 in controlling BMP/Smad signaling, which we find to be essential for maintaining low expression levels of several non-epidermal genes. P63 represses transcription of the inhibitory Smad7, thereby sustaining BMP signaling. In the absence of p63, compromised BMP signaling leads to inappropriate non-epidermal gene expression in postnatal mouse keratinocytes and in embryonic epidermis. Reactivation of BMP signaling by Smad7 knockdown and/or †"to a lesser extent†" by BMP treatment suppresses expression of non-epidermal genes in the absence of p63. Canonical BMP/Smad signaling is essential for control of non-epidermal genes as use of a specific inhibitor, or simultaneous knockdown of Smad1 and Smad5 counteract suppression of non-epidermal genes. Our data indicate that p63 prevents ectopic expression of non-epidermal genes by a conserved mechanism involving Smad7 repression and consequent enhancement of BMP/Smad signaling. Human syndromes caused by mutations in p63 gene resemble the phenotype of p63 knock-out mice characterized by ectodermal dysplasia, split hand/foot malformation and orofacial clefting. To understand the molecular defects of AEC syndrome, in our laboratory has been generated a knock-in mouse model for AEC syndrome. We searched for the expression of non-epidermal genes and known direct targets of p63 such as Bmp7 and Smad7 in AEC mutant mice. We found that neither non-epidermal genes or Bmp7 and Smad7 change their expression in this mouse model. Interestingly, we observed that known targets of p63 did not change their expression in AEC mutant mice. Here, we found that AEC mutation affects gene expression of small group of genes. Among them we identify p53 family members, p73 that is inhibited in AEC mutant epidermis demonstrating that p73 is a direct targets of p63.