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

Abstract

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 A y and the lethal non=agouti (a'q allele were not separated from a previously identified probe at the breakpoint of the IslGsO chromosomal rearrangement.Using the IslGsO 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 A y 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 A y are caused by ectopic activation of a signaling pathway similar to that used during normal hair growth.

Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

“…Furthermore, the results presented here show that mature A y /a mice are hyperinsulinemic and hyperleptinemic. This is also in line with previous findings (3,7,16,30), although these characteristics were milder in A y /a mice than in ob/ob mice (with the exception of hyperleptinemia). In the present study, we were not able to assess CART or AGRP protein levels and/or activity, because the amount of total protein recovered was too small.…”

“…Agouti protein has a potent antagonistic effect on hypothalamic MC4R (7, 30), and rodents become hyperphagic when signaling is interrupted (19,31). Lethal yellow (A y /a) mice display ectopic overexpression of agouti protein in the brain, which results in defective proopiomelanocortin (POMC)/MC4R signaling and, upon maturation, obesity (7,16,30,44). Because these obese mice are both hyperleptinemic and insensitive to exogenous leptin treatment (16, 44), they are thought to be in a "leptin-resistant state."…”

“…In contrast, infusion of agouti-related protein (AGRP) into the cerebroventricle accelerates the rate of rodent feeding (26,34,38), because AGRP is competitively antagonistic against ␣-melanocyte-stimulating hormone (␣-MSH), one of the end products of POMC, at levels of MC3R and MC4R (29,44). Overexpression of AGRP in transgenic mice (31) produces an obese phenotype similar to that of the MC4R knockout (19) or A y /a mice (7,30). Hypothalamic AGRP has also been found to downregulate the hypothalamo-pituitary-thyroid (HPT) axis through leptin-mediated effects on the HPT system (23).…”

Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity

“…Several mutations in mouse genes that lead to obesity have recently been characterized at the molecular level (1)(2)(3)(4)(5)(6)(7)(8). Further analysis of these genes and the use of mouse lines with mutations in these genes provides an opportunity to identify new therapeutic targets for the treatment of human obesity.…”

Seeing the gene therapy: application of gene gun technique to transfect and decolour pigmented rat skin with human agouti signalling protein cDNA

“…Most studies have proposed that ASP acts as an antagonist of MC1R, causing MC1R desensitization and consequent reduction of tyrosinase activity. 4,17 However, Scott et al 18 observed that ASP plays a role in the regulation of skin pigmentation through downregulation of MC1R mRNA transcription in cultured human melanocytes. Recently, microphthalmia transcription factor (MITF), which belong to the basic helix-loop-helix family, was found to regulate the gene for MC1R through its promoter region in cultured cells.…”