| ASIP | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | ASIP, AGSW, SHEP9, ASP, AGTIL, AGTI, agouti signaling protein | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:600201;MGI:87853;HomoloGene:1264;GeneCards:ASIP;OMA:ASIP - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Agouti-signaling protein is aprotein that in humans is encoded by the ASIPgene.[5][6] It is responsible for the distribution ofmelanin pigment in mammals.[7][8] Agouti interacts with themelanocortin 1 receptor to determine whether themelanocyte (pigment cell) producesphaeomelanin (a red to yellow pigment), oreumelanin (a brown to black pigment).[9] This interaction is responsible for making distinct light and dark bands in the hairs of animals such as theagouti, which the gene is named after. In other species such ashorses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will begrey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.[10]
The agouti-signaling protein (ASIP) is acompetitive antagonist withalpha-Melanocyte-stimulating hormone (α-MSH) to bind withmelanocortin 1 receptor (MC1R)proteins. Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.[11] This means where and whileagouti is being expressed, the part of the hair that is growing will come out yellow rather than black.
In mice, the agouti gene encodes aparacrine signalling molecule that causes hair folliclemelanocytes to synthesize the yellow pigmentpheomelanin instead of the black or brown pigmenteumelanin.Pleiotropic effects of constitutive expression of the mouse gene include adult-onsetobesity, increasedtumor 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 hairpigmentation, (2) act as an inverse agonist ofalpha-melanocyte-stimulating hormone, (3) play a role inneuroendocrine aspects ofmelanocortin action, and (4) have a functional role in regulating lipid metabolism inadipocytes.[12]
In mice, thewild typeagouti allele (A) presents a grey phenotype, however, many allele variants have been identified through genetic analyses, which result in a wide range of phenotypes distinct from the typical grey coat.[13] The most widely studied allele variants are thelethal yellow mutation (Ay) and theviable yellow mutation (Avy) which are caused by ectopic expression ofagouti.[13] These mutations are also associated withyellow obese syndrome which is characterized by early onsetobesity,hyperinsulinemia andtumorigenesis.[13][14] Themurineagouti gene locus is found on chromosome 2 and encodes a 131 amino acid protein. This protein signals the distribution ofmelanin pigments in epithelialmelanocytes located at the base of hair follicles with expression being more sensitive on ventral hair than on dorsal hair.[15][16]Agouti is not directly secreted in the melanocyte as it works as aparacrine factor on dermal papillae cells to inhibit release ofmelanocortin.[17] Melanocortin acts on follicular melanocytes to increase production ofeumelanin, a melanin pigment responsible for brown and black hair. Whenagouti is expressed, production ofpheomelanin dominates, a melanin pigment that produces yellow or red colored hair.[18]
Agouti signalling peptide adopts aninhibitor cystine knot motif.[19] Along with the homologousAgouti-related peptide, these are the only known mammalian proteins to adopt this fold.The peptide consists of 131 amino acids.[20]
Thelethal yellow mutation (Ay) was the first embryonic mutation to be characterized in mice, as homozygouslethal yellow mice (Ay/ Ay) die early in development, due to an error introphectoderm differentiation.[15]Lethal yellow homozygotes are rare today, whilelethal yellow andviable yellow heterozygotes (Ay/a and Avy/a) remain more common. In wild-type miceagouti is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in othertissues as well.[10] Thisectopic expression of theagouti gene is associated with theyellow obese syndrome, characterized by early onsetobesity,hyperinsulinemia andtumorigenesis.[15]
Thelethal yellow (Ay) mutation is due to an upstream deletion at the start site ofagouti transcription. This deletion causes the genomic sequence ofagouti to be lost, except thepromoter and the first non-encoding exon ofRaly, a ubiquitously expressed gene in mammals.[16] The codingexons ofagouti are placed under the control of theRaly promoter, initiating ubiquitous expression ofagouti, increasing production ofpheomelanin overeumelanin and resulting in the development of a yellow phenotype.[21]
Theviable yellow (Avy) mutation is due to a change in the mRNA length ofagouti, as the expressed gene becomes longer than the normal gene length of agouti. This is caused by the insertion of a single intracisternal A particle (IAP) retrotransposon upstream to the start site ofagouti transcription.[22] In the proximal end of the gene, an unknown promoter then causesagouti to be constitutionally activated, and individuals to present with phenotypes consistent with thelethal yellow mutation. Although the mechanism for the activation of the promoter controlling theviable yellow mutation is unknown, the strength of coat color has been correlated with the degree of genemethylation, which is determined by maternal diet and environmental exposure.[22] Asagouti itself inhibits melanocortin receptors responsible for eumelanin production, the yellow phenotype is exacerbated in bothlethal yellow andviable yellow mutations asagouti gene expression is increased.
Viable yellow (Avy/a) andlethal yellow (Ay/a) heterozygotes have shortened life spans and increased risks for developing early onset obesity,type II diabetes mellitus and various tumors.[17][23] The increased risk of developing obesity is due to the dysregulation of appetite, asagouti agonizes theagouti-related protein (AGRP), responsible for the stimulation of appetite via hypothalamic NPY/AGRP orexigenic neurons.[22] Agouti also promotes obesity by antagonizingmelanocyte-stimulating hormone (MSH) at the melanocortin receptor (MC4R), asMC4R is responsible for regulating food intake by inhibiting appetite signals.[24] The increase in appetite is coupled to alterations in nutrient metabolism due to theparacrine actions of agouti on adipose tissue, increasing levels of hepaticlipogenesis, decreasing levels oflipolysis and increasing adipocyte hypertrophy.[25] This increases body mass and leads to difficulties with weight loss as metabolic pathways become dysregulated.Hyperinsulinemia is caused by mutations toagouti, as the agouti protein functions in a calcium dependent manner to increase insulin secretion in pancreatic beta cells, increasing risks ofinsulin resistance.[26] Increased tumor formation is due to the increased mitotic rates ofagouti, which are localized to epithelial and mesenchymal tissues.[21]
Correct functioning ofagouti requires DNA methylation. Methylation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element in theviable yellow mutation.[23] Methylation on a gene causes the gene to not be expressed because it will cause thepromoter to be turned off. In utero, the mother's diet can cause methylation or demethylation. When this area is unmethylated, ectopic expression ofagouti occurs, and yellow phenotypes are shown because the phaeomelanin is expressed instead of eumelanin. When the region is methylated,agouti is expressed normally, and grey and brown phenotypes (eumelanin) occur. The epigenetic state of the IAP element is determined by the level of methylation, as individuals show a wide range of phenotypes based on their degree of DNA methylation.[23] Increased methylation is correlated with increased expression of the normalagouti gene. Low levels of methylation can inducegene imprinting which results in offspring displaying consistent phenotypes to their parents, as ectopic expression ofagouti is inherited through non-genomic mechanisms.[22][27]
DNA methylation is determinedin utero by maternal nutrition and environmental exposure.[23] Methyl is synthesizedde novo but attained through the diet by folic acid, methionine, betaine, and choline, as these nutrients feed into a consistent metabolic pathway for methyl synthesis.[28] Adequatezinc andvitamin B12 are required for methyl synthesis as they act as cofactors for transferring methyl groups.[6]
When inadequate methyl is available during early embryonic development, DNA methylation cannot occur, which increases ectopic expression ofagouti and results in the presentation of thelethal yellow andviable yellow phenotypes which persist into adulthood. This leads to the development of theyellow obese syndrome, which impairs normal development and increases susceptibility to the development of chronic disease. Ensuring maternal diets are high in methyl equivalents is a key preventive measure for reducing ectopic expression ofagouti in offspring. Diet intervention through methyl supplementation reduces imprinting at theagouti locus, as increased methyl consumption causes the IAP element to become completely methylated and ectopic expression ofagouti to be reduced.[29] This lowers the proportion of offspring that present with the yellow phenotype and increases the number offspring that resembleagouti wild type mice with grey coats.[22] Two genetically identical mice could look very different phenotypically due to the mothers' diets while the mice were in utero. If the mice has the agouti gene it can be expressed due to the mother eating a typical diet and the offspring would have a yellow coat. If the same mother had eaten a methyl-rich diet supplemented with zinc, vitamin B12, and folic acid then the offspring's agouti gene would likely become methylated, it wouldn't be expressed, and the coat color would be brown instead. In mice, the yellow coat color is also associated with health problems in mice including obesity and diabetes.[30]
Agouti signaling protein (ASP) is the human homologue of murineagouti. It is encoded by the human agouti gene onchromosome 20 and is a protein consisting of 132 amino acids. It is expressed much more broadly than murineagouti and is found in adipose tissue, pancreas, testes, and ovaries, whereas murineagouti is solely expressed in melanocytes.[6] ASP has 85% similarity to the murine form ofagouti.[31] As ectopic expression of murineagouti leads to the development of theyellow obese syndrome, this is expected to be consistent in humans.[31] Theyellow obese syndrome increases the development of many chronic diseases, including obesity, type II diabetes mellitus and tumorigenesis.[13]
ASP has similar pharmacological activation to murineagouti, as melanocortin receptors are inhibited through competitive antagonism.[32] Inhibition of melanocortin by ASP can also be through non-competitive methods, broadening its range of effects.[21] The function of ASP differs to murineagouti. ASP effects the quality of hair pigmentation whereas murineagouti controls the distribution of pigments that determine coat color.[22] ASP has neuroendocrine functions consistent with murineagouti, as it agonizes viaAgRP neurons in the hypothalamus and antagonizes MSH at MC4Rs which reduce satiety signals. AgRP acts as an appetite stimulator and increases appetite while decreasing metabolism. Because of these mechanisms, AgRP may be linked to increased body mass and obesity in both humans and mice.[33] Over-expression of AgRP has been linked to obesity in males, while certain polymorphisms of AgRP have been linked to eating disorders likeanorexia nervosa.[34][35] The mechanism underlying hyperinsulinemia in humans is consistent with murineagouti, as insulin secretion is heightened through calcium sensitive signaling in pancreatic beta cells.[6] The mechanism for ASP induced tumorigenesis remains unknown in humans.[6]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
