Regulation of Melanogenesis by the Mouse Agouti Locus

Granholm, Nels

Abstract

The lethal yellow gene (A-y) of the mouse agouti locus represents a valuable experimental probe to dissect cellular and molecular processes involved in the regulation of melanogenesis. A-y may impair melanogenesis via aberrant synthesis and deployment of: (1) structural proteins comprising the matrix of pigment granules and (2) tyrosinase isozymes, integral components of pigment granules which catalyze the conversion of tyrosine to melanin. Modes of A-y gene expression will be analyzed structurally by means of transmission electron microscopy of pigment granules and biochemically via characterizing the multiple molecular forms (isozymes) of tyrosinase. Comprehensive morphological characterization of the stepwise ontogeny of granules within four different genotypes of hair bulb melanocytes should reveal genuine differences in morphogenetic patterns between A-y and a alleles. The precise chronology and nature of morphological specificity should yield clues to the underlying aberrant biochemistry. Polyacrylamide gel electrophoretic analyses of tyrosinases following Alpha-MSH and glycosylation inhibitions (e.g., tunicamycin) together with the direct biochemical measurement of tyrosinase activity should allow us to assess how A-y and a differ in their ability to direct the synthesis of isozymes of tyrosinase. Data from these studies should permit us to develop a more comprehensive understanding of A-y gene and agouti locus function. This new knowledge should contribute to an overall understanding of the regulation of mammalian gene expression. Since A-y also causes obesity and diabetes, knowledge of how A-y is regulated may also be helpful in explaining the etiology of these conditions. Current work on the familial hypercholesterolemia mutation in humans documents the significance of determining the primary biochemical lesions specified by valuable mutations.