Several lines of evidence suggest that sensory nerves ending at the skin have profound influences on their target, the epidermis. To test the hypothesis, we examined the consequences of denervation on the paw skin of rats by eliminating its innervation. We investigated temporal changes of nerve degeneration, keratinocyte proliferation and differentiation, gene expression, and epidermal thickness. Nerve terminals in the epidermis began to degenerate within 24 h after denervation. All epidermal nerves were completely degenerated by 2 d. During the interval of nerve degeneration, there was a significant reduction of bromodeoxyuridine incorporation from 24 h of nerve injury (39 +/- 7% of the control side, p 0.01). By 2 d, there was a further reduction of bromodeoxyuridine labeling (11 +/- 8%, p < 0. 0001). The incorporation of bromodeoxyuridine remained depressed when the skin was denervated (35 +/- 11%, p < 0.01). Four days after eliminating skin innervation, the denervated epidermis became thinner than the control epidermis (70 +/- 8% of the control, p < 0. 01). Epidermal thinning was associated with a significant decrease in expression of glyceraldehyde-3-phosphate dehydrogenase and beta-actin transcripts (33 +/- 8% of the control epidermis from postoperative day 4, p < 0.001). Other aspects of keratinocyte differentiation, including the patterns of keratin expression, and programmed cell death, were unaltered by skin denervation. These data indicate that skin denervation is sufficient to influence keratinocyte proliferation and therefore epidermal thickness.