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Nectins are immunoglobulin‐like cell adhesion molecules mainly localized in adherens junctions. The transcription factor p63 is a master regulator of gene expression in stratified epithelia and controls several molecular processes. As mutations in the  Pvrl1  and  Pvrl4  genes encoding for nectins cause genetic disorders with phenotypes similar to  p63 ‐related syndromes, we investigated whether these proteins might be under p63 transcriptional control. Here, we show that in  p63 ‐null skin,  Pvrl1  gene expression is strongly reduced, whereas  Pvrl4  expression is unaffected. In human and mouse primary keratinocytes p63 depletion leads to a specific downregulation of the  Pvrl1  gene. Consistent with a direct regulation, chromatin immunoprecipitation experiments (ChIP) indicate that p63 binds to two conserved intronic  Pvrl1  enhancer regions. Ankyloblepharon–ectodermal defects–cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder, caused by mutations in  p63  gene, mainly characterized by skin fragility. To test whether nectins may be affected in AEC syndrome, their expression was measured in keratinocytes obtained from patients with AEC or from a conditional mouse model for AEC syndrome.  Pvrl1  expression was reduced in AEC keratinocytes, consistent with impaired p63 function. Surprisingly,  Pvrl4  expression was similarly affected, in parallel with decreased expression of the transcription factor Irf6. Consistent with the well‐characterized role of Irf6 in keratinocyte differentiation and its strong downregulation in AEC syndrome, Irf6 depletion caused reduced expression of  Pvrl4  in wild‐type keratinocytes. Taken together, our results indicate that  Pvrl1  is a  bona fide  target gene of the transcription factor p63, whereas  Pvrl4  regulation is linked to epidermal differentiation and is under Irf6 control.

p63‐dependent and independent mechanisms of nectin‐1 and nectin‐4 regulation in the epidermis