DIFFERENTIAL-EFFECTS OF TOPICAL RETINOIC ACID APPLICATION ON KERATIN K1 AND FILAGGRIN EXPRESSION IN MOUSE EPIDERMIS

Retinoic acid (RA) modulates epidermal homeostasis and affects differe ntiation-associated proteins such as keratin K1 and filaggrin. Because results from in invitro and vivo studies have been conflicting with r espect to RA effects on keratinization, we examined the terminal diffe rentiation of epidermal cell cohorts after RA stimulation in vivo. Pul se-labelling with 5-bromo-2-deoxyuridine (BrdU) was performed by intra peritoneal injection of mice immediately or at 16 h after a single top ical application of 100 nmol RA. The cell cohort labelled at the time of RA application consisted of previously unperturbed cells exposed to RA after initiation of S-phase whereas the cohort labelled 16 hr afte r RA application consisted of cells stimulated into the S-phase by RA. These two cohorts of partially synchronized cells were followed for u p to 72 h after BrdU labelling. Such labelling combined with keratin K 1 or filaggrin expression was scored by paired immunofluorescence stai ning of skin sections. The onset of keratin K1 expression was unchange d in both series after RA treatment, while filaggrin appeared earlier than in controls. The differential effect of RA on the maturation mark ers was related to the proliferative activity, the increased cell turn over, and the shortened epidermal transit time. The onset of keratin e xpression appeared to be regulated before the postmitotic period, wher eas filaggrin expression appeared to be regulated during the late phas e of the maturation process, thus being influenced by the actual epide rmal kinetics and structural alterations. These results suggested that the effect of the RA on epidermal differentiation is secondary to its effect of RA on epidermal differentiation is secondary to its effect on proliferation, as determined by the altered cellular age distributi on following regenerative proliferation.