Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation

The mouse agouti gene controls the deposition of yellow and black pigment in developing hairs. Several dominant alleles, including lethal yellow (Ay), result in the exclusive production of yellow pigment and have pleiotropic effects that include obesity and increased tumor susceptibility. In an inte...

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Bibliographic Details
Published in:Genes & development 1993-03, Vol.7 (3), p.454-467
Main Authors: MILLER, M. W, DUHL, D. M. J, VRIELING, H, CORDES, S. P, OLLMANN, M. M, WINKES, B. M, BARSH, G. S
Format: Article
Language:English
Subjects:
Agouti Signaling Protein
Amino Acid Sequence
Animals
Base Sequence
Biological and medical sciences
Classical genetics, quantitative genetics, hybrids
Cloning, Molecular
Cosmids
Crosses, Genetic
DNA - genetics
Embryo, Mammalian
Female
Fundamental and applied biological sciences. Psychology
Genes, Lethal
Genetics of eukaryotes. Biological and molecular evolution
Hair Color - genetics
In Situ Hybridization
Intercellular Signaling Peptides and Proteins
Male
Mice
Mice, Mutant Strains
Molecular Sequence Data
Mutation
Oligodeoxyribonucleotides
Proteins - genetics
Recombination, Genetic
Restriction Mapping
Sequence Homology, Nucleic Acid
Vertebrata
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Summary:The mouse agouti gene controls the deposition of yellow and black pigment in developing hairs. Several dominant alleles, including lethal yellow (Ay), result in the exclusive production of yellow pigment and have pleiotropic effects that include obesity and increased tumor susceptibility. In an interspecific backcross, we established genetic limits for the agouti gene and found that the Ay and the lethal non-agouti (ax) allele were not separated from a previously identified probe at the breakpoint of the Is1GsO chromosomal rearrangement. Using the Is1GsO probe, we isolated the agouti gene, and find that it has the potential to code for a secreted protein expressed in hair follicles and the epidermis, and that the level of expression correlates with the synthesis of yellow pigment. In the Ay mutation, there is a chromosomal rearrangement that results in the production of a chimeric RNA expressed in nearly every tissue of the body. The 5' portion of this chimeric RNA contains highly expressed novel 5' sequences, but the 3' portion retains the protein-coding potential of the nonmutant allele. We speculate that dominant pleiotropic effects of Ay are caused by ectopic activation of a signaling pathway similar to that used during normal hair growth.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.7.3.454