Foxn1 promotes keratinocyte differentiation by regulating the activity of protein kinase C.

The transcription factor Foxn1 (the product of the nude locus) promotes the terminal differentiation of epithelial cells in the epidermis and hair follicles. Activated early in terminal differentiation, Foxn1 can modulate the timing or order of trait acquisition, as it induces early features of epidermal differentiation while suppressing late features. Here, we identify protein kinase C (PKC) as a key target of Foxn1 in keratinocyte differentiation control. Foxn1 has broad negative effects on the PKC family, as the loss of Foxn1 function leads to higher levels of total, primed, and activated PKC. Phosphorylated PKC substrates (the mediators of PKC function) rise when Foxn1 is inactivated and fall when Foxn1 is overproduced, suggesting that Foxn1 antagonizes PKC's effects. When PKC inhibitors are applied to nude (Foxn1 null) keratinocytes, nude defects are normalized or suppressed, as the inhibitors prevent nude cells from underproducing early differentiation markers and overproducing late markers. Taken together, the results suggest that Foxn1 acts as a restraint or brake on PKC signaling and that without this brake PKC disrupts differentiation. The results further suggest that Foxn1 modulates stage-specific markers by modulating PKC activity, providing control over the timing of steps in the differentiation program.