Cellular Retinoic Acid-Binding Proteins (CRABPs) deficient mice are grossly normal. This indicates that the role of CRABPs is not essential in morphogenesis. However since CRABPs are highly conserved proteins, their absence may result in subtle alteration of skin homeostasis. We have studied the tail skin of adult mice with deleted gene for each of the two CRABPs (CRABPs-KO). Skin retinoid content (Rp-HPLC) was similar in CRABPs-KO and wild type mice (WT) showing no detectable retinoic acid (limit 5 ng/g ww) and similar amounts of retinol (65±12 and 55±2 ng/g ww) and retinyl esters (50±9 and 54±14 ng/g ww) respectively, indicating that no excess in RA and metabolites result from total CRABP deficiency. Gene expression of structural keratinocyte differentiation proteins such as keratins 50-, 65, 70 kDa, loricrin and filaggrin were identical in CRABPs-KO and WT. BrdU positive cells (/100 interfollicular zones, mean±sem) were 255±45 in CRABPs-KO versus 146±45 (p=0.04) in WT. c-jun and c- fos mRNAs (northern blot) were both increased (1.8-fold) in CRABPs-KO. TNF-α (Wehi bioassay) was 1842±313 pg/ml in CRABPs-KO versus 821±176 in WT (p=0.029). p53 mRNA (RT PCR) was increased 2-fold and p21 W a f 1 / C i p 1 4-fold (p<0.001) in CRABPs-KO versus WT. The subtle alterations in the expression of genes involved in the control of cell cycle as well as the increased number of DNA synthesizing basal cells that we have identified in the epidermis of CRABPs deficient mice suggest that these proteins may be physiologically involved in directing retinoic acid function towards antiproliferative pathway.