Genomic organization and molecular genetics of the agouti locus in the mouse

The agouti locus regulates a switch in pigment synthesis by hair bulb melanocytes between eumelanosomes and phaeomelanosomes. The agouti locus appears to encode a trans-acting product that acts within the hair follicle to direct the pigment synthesis of melanocytes. In addition to coat color, several agouti mutations affect development, obesity, and susceptibility to neoplasms. The genomic organization of the agouti region suggests that there are three functional units involved in prenatal lethality flanking the agouti coat color locus. Molecular probes for the agouti region are needed to identify and study the genes responsible for these pleiotropic effects. Classical genetic crosses coupled with molecular genetic analyses have been used to determine the map distance and orientation of molecular loci in the agouti region of mouse chromosome 2. The proximity of some of these molecular probes to the agouti region enables the use of molecular markers designed to clone sequences from the agouti locus. Pulsed-field gel electrophoresis is being used to establish long-range restriction maps surrounding the agouti region. Identification of DNA alterations corresponding to specific agouti mutations will enable determination of the molecular basis of agouti locus phenotypes. The mechanism by which the agouti gene product(s) tells the melanocyte what type of pigment to produce may involve cell-cell communication and signal transduction pathways. Future experiments will determine the type of protein(s) encoded by the agouti coat color locus and establish the mechanism by which these protein(s) control the nature and timing of pigment production by melanocytes in the hair follicle.