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General Comment |
The agouti gene on mouse chromosome 2 encodes a paracrine signaling molecule that The mouse agouti coat color gene encodes a novel paracrine signaling molecule whose pulsatile expression causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment eumelanin. Consequently, agouti mice produce hairs with a subapical yellow band on an otherwise black or brown background when expressed during the midportion of hair growth. This produces a characteristic pattern of banded pigment in individual hairs. Several spontaneous agouti alleles produce adult-onset obesity and diabetes, and have provided important single-gene animal models for alterations in energy metabolism.
NCBI Summary:
In mice, the agouti gene encodes a paracrine signaling molecule that causes hair follicle melanocytes to synthesize pheomelanin, a yellow pigment, instead of the black or brown pigment, eumelanin. Pleiotropic effects of constitutive expression of the mouse gene include adult-onset obesity, increased tumor susceptibility, and premature infertility. This gene is highly similar to the mouse gene and encodes a secreted protein that may (1) affect the quality of hair pigmentation, (2) act as a pharmacological antagonist of alpha-melanocyte-stimulating hormone, (3) play a role in neuroendocrine aspects of melanocortin action, and (4) have a functional role in regulating lipid metabolism in adipocytes.
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Comment |
Wilson et al. (1995) cloned the human homolog of the mouse agouti gene from a human chromosome 20 yeast artificial chromosome known to contain S-adenosyl homocysteine hydrolase (AHCY). The human agouti gene, named Agouti Signaling Protein (ASP), encodes a 132 amino acid protein, the mRNA for which is expressed in testis, ovary, and heart, and at lower levels in liver, kidney, and foreskin. The expression of ASP in cell culture blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melanoma cells. The expression of ASP in human tissues suggests a function for agouti homologs in species that do not exhibit the characteristic phenotype of banded hairs.
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Mutations |
3 mutations
Species: mouse
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: In most mice, agouti is expressed at highest levels in skin and is under control of hair cycle- and ventral-specific promoters, which together produce a light-bellied phenotype, i.e., a combination of yellow ventral hairs and banded dorsal hairs. In several mouse mutations, such as 'lethal yellow' and 'viable yellow,' agouti is deregulated and expressed ectopically. Expression throughout hair growth and in nearly every tissue of the body produces a yellow coat and pleiotropic effects that
include adult-onset obesity, increased tumor susceptibility, and premature infertility.
Species: mouse
Mutation name: None
type: targeted overexpression
fertility: subfertile
Comment: As predicted by the interactions of mouse agouti with the extension gene (which encodes the melanocyte receptor for alpha-melanocyte stimulating hormone alpha-MSH]), expression of ASP in transgenic mice produces a yellow coat [(Wilson et al., 1995).
Species: mouse
Mutation name: None
type: targeted overexpression
fertility: subfertile
Comment: Mice that carry the lethal yellow (Ay) or viable yellow (Avy) mutation, two dominant mutations of the agouti (a) gene in mouse chromosome 2, exhibit a phenotype that includes yellow fur, marked obesity, a form of type II diabetes associated with insulin resistance, and an increased susceptibility to tumor development. Molecular analyses of these and several other dominant "obese yellow" a-locus mutations suggested that ectopic expression of the normal agouti protein gives rise to this
complex pleiotropic phenotype. (Klebig et al., 1995) tested this hypothesis directly by generating transgenic mice that ectopically express an agouti cDNA clone encoding the normal agouti protein in all tissues examined. Transgenic mice of both sexes have yellow fur, become obese, and develop hyperinsulinemia. These results demonstrate conclusively that the ectopic agouti expression is responsible for most, if not all, of the phenotypic traits of the dominant, obese yellow mutants.
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