Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice

Epidermal development requires the transcription factor p63, as p63-/- mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (Delta Np63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63 alpha and/or Delta Np63 alpha under the K5 promoter into p63-/- mice by in vivo genetic complementation. Whereas p63-/- and p63-/-; TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63-/-; DN mice showed significant epidermal basal layer formation. Double TAp63 alpha/ DNp63 alpha complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, Delta Np63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.