Agouti protein and Agouti-related protein (Agrp) are paracrine-signaling molecules that normally regulate pigmentation and body weight, respectively. These proteins antagonize the effects of ␣-melanocyte-stimulating hormone (␣-MSH) and other melanocortins, and several alternatives have been proposed to explain their biochemical mechanisms of action. We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity. In melanophores, Agouti protein has no effect in the absence of ␣-MSH, but its action cannot be explained solely by inhibition of ␣-MSH binding. In

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White spotting is the absence of melanocytes (pigment cells) from part or all of the locations in the body where they are normally found. At least in the case of the W (kit) locus, white spotting has been attributed to apoptosis. In addition to the death of melanoblasts, white spotting might result from their failure to migrate to their normal locations. These developmental failures are known to be melanocyte-specific in some instances and environment-specific in others. The environment is defined as the tissues surrounding the melanoblast. Patterns of white spotting were examined on mice mutant at the piebald (s), patch (Ph), dominant spotting (W(J2)) rumpwhite (Rw) or belted (bt) loci. The dominant spotting locus has been cloned and found to encode KIT; it has been suggested that Patch encodes the linked alpha-PDGF receptor. Piebald encodes the endothelin beta receptor. In each case, the phenotypes expressed when the allele was backcrossed onto one inbred strain C57BL/6 (B6), were compared with phenotypes expressed when the allele was backcrossed onto a different inbred strain, JU/CtLm (JU). The literature documents genetic loci that influence the extent of the white spotted area; we herein demonstrate that genetic loci also influence the location where the white spot (absence of melanocytes) will occur over the body of the mouse. Spotting occurs in a more anterior direction on JU mice that are piebald, patch or dominant-spotted compared with similar B6 mice. The relationship is reversed in rumpwhite mice, where white spotting is more anterior in the C57BL/6 mice than in the JU mice. The spotting pattern of belted mice was not modified by the background genome. Thus, the Mendelian observations indicate that several loci, which differ in JU compared with B6 mice, influence the size and the location of white spots on the mouse.