The melanocortin 1 receptor (Mc1r) plays a central role in cutaneous biology, 
but is expressed at very low levels by a small fraction of cells in the skin. In 
humans, loss-of-function MC1R mutations cause fair skin, freckling, red hair, 
and increased predisposition to melanoma; in mice, Mc1r loss-of-function is 
responsible for the recessive yellow mutation, associated with pheomelanic hair 
and a decreased number of epidermal melanocytes. To better understand how Mc1r 
signaling affects different cutaneous phenotypes, we examined large-scale 
patterns of gene expression in different skin components (whole epidermal 
sheets, basal epidermal cells and whole skins) of neonatal (P2.5) normal and 
recessive yellow mice, starting with a 26K mouse cDNA microarray. From c. 17 000 
genes whose levels could be accurately measured in neonatal skin, we identified 
883, 2097 and 552 genes that were uniquely expressed in the suprabasal 
epidermis, basal epidermis and dermis, respectively; specific biologic roles 
could be assigned for each class. Comparison of normal and recessive yellow mice 
revealed 69 differentially expressed genes, of which the majority had not been 
previously implicated in Mc1r signaling. Surprisingly, many of the 
Mc1r-dependent genes are expressed in cells other than melanocytes, even though 
Mc1r expression in the skin is confined almost exclusively to epidermal 
melanocytes. These results reveal new targets for Mc1r signaling, and point to a 
previously unappreciated role for a Mc1r-dependent paracrine effect of 
melanocytes on other components of the skin.