Doctoral Dissertations

Date of Award

5-1994

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biomedical Sciences

Major Professor

Rick Woyonik

Committee Members

Richard Mural, Gene Rinchik, Lee Russell

Abstract

The agouti locus in mouse chromosome 2 regulates the differential production of eumelanin (black or brown) and phaeomelanin (yellow) pigment granules. Agouti coloration, which is the true wild-type coat color of mice, arises because the individual hair shafts are black or brown with a subapical yellow band. Over 20 distinct alleles have been identified that form an intricate dominance hierarchy and account for an array of different phenotypes. Unlike most coat-color genes, which act in a cell-autonomous manner within the melanocyte, the agouti locus functions from within the microenvironment of the hair follicle, suggesting that the agouti gene product participates in an intercellular signaling pathway. The objective of this dissertation was to learn more about agouti-locus function by analyzing it at the molecular level. I utilized a radiation-induced mutation to gain molecular access to the mouse agouti locus. Characterization of genomic and cDNA clones revealed that agouti is a large, complex locus that consists of a single gene that spans over 100 kb of DNA and encodes a novel 131 amino acid protein. The agouti gene is normally expressed in skin, and more importantly, its structure and expression are disrupted in a number of mutant alleles. Furthermore, this gene produces several alternately processed transcripts that differ in their 5' untranslated regions but splice to the same coding sequence. These different forms of mRNA are differentially expressed within the skin, particularly over the dorsoventral surface of the animal. A model is presented that describes how the agouti protein, which appears to be secreted, might signal melanocytes to produce eumelanin or phaeomelanin. Additionally, ectopic overexpression of the agouti gene in several dominant mutants is responsible for a pleiotropic syndrome that includes an all-yellow coat, diabetes, obesity, and an increased susceptibility to tumors. Finally, using a cross-species hybridization approach, I was able to isolate the human agouti gene. It shares considerable sequence homology with the mouse gene and maps to chromosome 20q11; its potential role in human hair pigmentation and diabetes is discussed.

Download
Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS