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The '''agouti gene''' encodes the [[agouti-signaling protein]] (ASIP), responsible for the distribution of [[melanin]] pigment in mammals.<ref>{{cite journal | vauthors = Silvers WK, Russell ES |title=An experimental approach to action of genes at the ''agouti'' locus in the mouse |journal=Journal of Experimental Zoology |date=1955 |volume=130 |issue=2 |pages=199–220 |doi=10.1002/jez.1401300203}}</ref><ref>{{cite journal | vauthors = Millar SE, Miller MW, Stevens ME, Barsh GS | title = Expression and transgenic studies of the mouse agouti gene provide insight into the mechanisms by which mammalian coat color patterns are generated | journal = Development | volume = 121 | issue = 10 | pages = 3223–32 | date = October 1995 | pmid = 7588057 }}</ref> Agouti interacts with the [[melanocortin 1 receptor]] to determine whether the [[melanocyte]] (pigment cell) produces the yellow to red [[phaeomelanin]], or the brown to black [[eumelanin]].<ref>{{cite journal | vauthors = Voisey J, van Daal A | title = Agouti: from mouse to man, from skin to fat | journal = Pigment Cell Research | volume = 15 | issue = 1 | pages = 10–8 | date = February 2002 | pmid = 11837451 | doi = 10.1034/j.1600-0749.2002.00039.x }}</ref> This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the [[agouti]]. In other species such as [[horse]]s, it determines what parts of the body are red or black.
The '''agouti gene''' encodes the [[agouti-signaling protein]] (ASIP), responsible for the distribution of [[melanin]] pigment in mammals.<ref>{{cite journal | vauthors = Silvers WK, Russell ES |title=An experimental approach to action of genes at the ''agouti'' locus in the mouse |journal=Journal of Experimental Zoology |date=1955 |volume=130 |issue=2 |pages=199–220 |doi=10.1002/jez.1401300203}}</ref><ref>{{cite journal | vauthors = Millar SE, Miller MW, Stevens ME, Barsh GS | title = Expression and transgenic studies of the mouse agouti gene provide insight into the mechanisms by which mammalian coat color patterns are generated | journal = Development | volume = 121 | issue = 10 | pages = 3223–32 | date = October 1995 | pmid = 7588057 }}</ref> Agouti interacts with the [[melanocortin 1 receptor]] to determine whether the [[melanocyte]] (pigment cell) produces [[phaeomelanin]] (a red to yellow pigment), or [[eumelanin]] (a brown to black pigment).<ref>{{cite journal | vauthors = Voisey J, van Daal A | title = Agouti: from mouse to man, from skin to fat | journal = Pigment Cell Research | volume = 15 | issue = 1 | pages = 10–8 | date = February 2002 | pmid = 11837451 | doi = 10.1034/j.1600-0749.2002.00039.x }}</ref> This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the [[agouti]]. In other species such as [[horse]]s, the agouti gene is responsible for determining which parts of the horse will be black. Horses can either have black distributed across its body or can have black only in certain locations such as the tail, ears, mane, and the lower legs.<ref>{{Cite web|url=https://www.animalgenetics.us/equine/coat_color/Agouti.asp|title=Agouti Gene {{!}} Genetic Testing {{!}} Animal Genetics|website=www.animalgenetics.us|access-date=2019-11-14}}</ref>


The [[agouti-signaling protein]] (ASIP) competes with [[alpha-Melanocyte-stimulating hormone]] (α-MSH) to bind with [[melanocortin 1 receptor]] (MC1R) [[protein]]s. Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.<ref name=OMIM-ASIP>{{OMIM|600201}}</ref>
The [[agouti-signaling protein]] (ASIP) is a [[Agonist|competitive agonist]] with [[alpha-Melanocyte-stimulating hormone]] (α-MSH) to bind with [[melanocortin 1 receptor]] (MC1R) [[protein]]s. Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.<ref name=OMIM-ASIP>{{OMIM|600201}}</ref>


In mice, the [[wild type]] ''agouti'' 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.<ref name="Bultman">{{cite journal | vauthors = Bultman SJ, Michaud EJ, Woychik RP | title = Molecular characterization of the mouse agouti locus | journal = Cell | volume = 71 | issue = 7 | pages = 1195–204 | date = December 1992 | pmid = 1473152 | doi = 10.1016/S0092-8674(05)80067-4 }}</ref> The most widely studied allele variants are the ''lethal yellow'' mutation (A<sup>y</sup>) and the ''viable yellow'' mutation (A<sup>vy</sup>) which are caused by ectopic expression of ''agouti''.<ref name="Bultman"/> These mutations are synonymous with the ''yellow obese syndrome'' which is characterized by early onset [[obesity]], [[hyperinsulinemia]] and [[tumorigenesis]].<ref name="Bultman"/><ref name="Wolff">{{cite journal | vauthors = Wolff GL, Roberts DW, Mountjoy KG | title = Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome | journal = Physiological Genomics | volume = 1 | issue = 3 | pages = 151–63 | date = November 1999 | pmid = 11015573 | doi = 10.1152/physiolgenomics.1999.1.3.151 }}</ref>
In mice, the [[wild type]] ''agouti'' 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.<ref name="Bultman">{{cite journal | vauthors = Bultman SJ, Michaud EJ, Woychik RP | title = Molecular characterization of the mouse agouti locus | journal = Cell | volume = 71 | issue = 7 | pages = 1195–204 | date = December 1992 | pmid = 1473152 | doi = 10.1016/S0092-8674(05)80067-4 }}</ref> The most widely studied allele variants are the ''lethal yellow'' mutation (A<sup>y</sup>) and the ''viable yellow'' mutation (A<sup>vy</sup>) which are caused by ectopic expression of ''agouti''.<ref name="Bultman"/> These mutations are synonymous with the ''yellow obese syndrome'' which is characterized by early onset [[obesity]], [[hyperinsulinemia]] and [[tumorigenesis]].<ref name="Bultman"/><ref name="Wolff">{{cite journal | vauthors = Wolff GL, Roberts DW, Mountjoy KG | title = Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome | journal = Physiological Genomics | volume = 1 | issue = 3 | pages = 151–63 | date = November 1999 | pmid = 11015573 | doi = 10.1152/physiolgenomics.1999.1.3.151 }}</ref>
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==Pigment development==
==Pigment development==
The murine ''agouti'' gene locus is found on chromosome 2 and encodes a 131 amino acid protein. This protein signals the distribution of [[melanin]] pigments in epithelial [[melanocyte]]s located at the base of hair follicles.<ref name="Mayer">{{cite journal | vauthors = Mayer TC, Fishbane JL | title = Mesoderm-ectoderm interaction in the production of the agouti pigmentation pattern in mice | journal = Genetics | volume = 71 | issue = 2 | pages = 297–303 | date = June 1972 | pmid = 4558326 | pmc = 1212784 | url = https://www.genetics.org/content/genetics/71/2/297.full.pdf }}</ref> Expression is more sensitive on ventral hair than dorsal hair.<ref name="Melmed">{{cite book |last1=Melmed |first1=S. (Ed) |title=The Pituitary |date=2010 |publisher=Academic Press |location=Cambridge: MA |edition=3rd}}</ref> ''Agouti'' is not directly secreted in the melanocyte as it works as a [[paracrine]] factor on dermal papillae cells to inhibit release of [[melanocortin]].<ref name="Miltenberger">{{cite journal | vauthors = Miltenberger RJ, Mynatt RL, Wilkinson JE, Woychik RP | title = The role of the agouti gene in the yellow obese syndrome | journal = The Journal of Nutrition | volume = 127 | issue = 9 | pages = 1902S–1907S | date = September 1997 | pmid = 9278579 | doi = 10.1093/jn/127.9.1902S }}</ref> Melanocortin acts on follicular melanocytes to increase production of [[eumelanin]], a melanin pigment responsible for brown and black hair. When ''agouti'' is expressed, production of [[phaeomelanin]] dominates, a melanin pigment that produces yellow or red colored hair.<ref name="Lu">{{cite journal | vauthors = Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO | title = Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor | journal = Nature | volume = 371 | issue = 6500 | pages = 799–802 | date = October 1994 | pmid = 7935841 | doi = 10.1038/371799a0 | bibcode = 1994Natur.371..799L }}</ref> The dominance hierarchy of pigment expression explains the evolutionary persistence of the yellow phenotype of ''agouti'', as [[pheomelanin]] expression always dominates over [[eumelanin]] expression.<ref name="Mayer" />
The [[Murinae|murine]] ''agouti'' gene locus is found on chromosome 2 and encodes a 131 amino acid protein. This protein signals the distribution of [[melanin]] pigments in epithelial [[melanocyte]]s located at the base of hair follicles.<ref name="Mayer">{{cite journal | vauthors = Mayer TC, Fishbane JL | title = Mesoderm-ectoderm interaction in the production of the agouti pigmentation pattern in mice | journal = Genetics | volume = 71 | issue = 2 | pages = 297–303 | date = June 1972 | pmid = 4558326 | pmc = 1212784 | url = https://www.genetics.org/content/genetics/71/2/297.full.pdf }}</ref> Expression is more sensitive on ventral hair than dorsal hair.<ref name="Melmed">{{cite book |last1=Melmed |first1=S. (Ed) |title=The Pituitary |date=2010 |publisher=Academic Press |location=Cambridge: MA |edition=3rd}}</ref> ''Agouti'' is not directly secreted in the melanocyte as it works as a [[paracrine]] factor on dermal papillae cells to inhibit release of [[melanocortin]].<ref name="Miltenberger">{{cite journal | vauthors = Miltenberger RJ, Mynatt RL, Wilkinson JE, Woychik RP | title = The role of the agouti gene in the yellow obese syndrome | journal = The Journal of Nutrition | volume = 127 | issue = 9 | pages = 1902S–1907S | date = September 1997 | pmid = 9278579 | doi = 10.1093/jn/127.9.1902S }}</ref> Melanocortin acts on follicular melanocytes to increase production of [[eumelanin]], a melanin pigment responsible for brown and black hair. When ''agouti'' is expressed, production of [[phaeomelanin]] dominates, a melanin pigment that produces yellow or red colored hair.<ref name="Lu">{{cite journal | vauthors = Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO | title = Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor | journal = Nature | volume = 371 | issue = 6500 | pages = 799–802 | date = October 1994 | pmid = 7935841 | doi = 10.1038/371799a0 | bibcode = 1994Natur.371..799L }}</ref> The dominance hierarchy of pigment expression explains the evolutionary persistence of the yellow phenotype of ''agouti'', as [[pheomelanin]] expression always dominates over [[eumelanin]] expression.<ref name="Mayer" />


==Mutations==
==Mutations==
The ''lethal yellow'' mutation (A<sup>y</sup>) was the first embryonic mutation to be characterized in mice, as homozygous ''lethal yellow'' mice (A<sup>y</sup>/ A<sup>y</sup>) die early in development, due to an error in trophectoderm differentiation.<ref name="Mayer" /> ''Lethal yellow'' homozygotes are rare today, while ''lethal yellow'' and ''viable yellow'' heterozygotes (A<sup>y</sup>/a and A<sup>vy</sup>/a) remain more common. In wild-type mice ''agouti'' is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in other [[tissue (biology)|tissues]] as well.<ref name=Klebig1995>{{cite journal | vauthors = Klebig ML, Wilkinson JE, Geisler JG, Woychik RP | title = Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4728–32 | date = May 1995 | pmid = 7761391 | pmc = 41780 | doi = 10.1073/pnas.92.11.4728 | bibcode = 1995PNAS...92.4728K }}</ref> This [[ectopic expression]] of the ''agouti'' gene is associated with the ''yellow obese syndrome'', characterized by early onset [[obesity]], [[hyperinsulinemia]] and [[tumorigenesis]].<ref name="Mayer"/>
The ''lethal yellow'' mutation (A<sup>y</sup>) was the first embryonic mutation to be characterized in mice, as homozygous ''lethal yellow'' mice (A<sup>y</sup>/ A<sup>y</sup>) die early in development, due to an error in [[Trophoblast|trophectoderm]] differentiation.<ref name="Mayer" /> ''Lethal yellow'' homozygotes are rare today, while ''lethal yellow'' and ''viable yellow'' heterozygotes (A<sup>y</sup>/a and A<sup>vy</sup>/a) remain more common. In wild-type mice ''agouti'' is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in other [[tissue (biology)|tissues]] as well.<ref name=Klebig1995>{{cite journal | vauthors = Klebig ML, Wilkinson JE, Geisler JG, Woychik RP | title = Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4728–32 | date = May 1995 | pmid = 7761391 | pmc = 41780 | doi = 10.1073/pnas.92.11.4728 | bibcode = 1995PNAS...92.4728K }}</ref> This [[ectopic expression]] of the ''agouti'' gene is associated with the ''yellow obese syndrome'', characterized by early onset [[obesity]], [[hyperinsulinemia]] and [[tumorigenesis]].<ref name="Mayer"/>
The ''lethal yellow'' (A<sup>y</sup>) mutation is due to an upstream deletion at the start site of ''agouti'' transcription. This deletion causes the genomic sequence of ''agouti'' to be lost, except the promoter and the first non-encoding exon of ''Raly'', a ubiquitously expressed gene in mammals.<ref name="Melmed"/> The coding exons of ''agouti'' are placed under the control of the ''Raly'' promoter, initiating ubiquitous expression of ''agouti'', increasing production of [[pheomelanin]] over [[eumelanin]] and resulting in the development of a yellow phenotype.<ref name="Tollefsbol">{{cite book |last1=Tollefsbol |first1=T. (Ed.) |title=Epigenetics in Human Disease |date=2012 |publisher=Academic Press |location=Cambridge: MA |edition=6}}</ref>
The ''lethal yellow'' (A<sup>y</sup>) mutation is due to an upstream deletion at the start site of ''agouti'' transcription. This deletion causes the genomic sequence of ''agouti'' to be lost, except the promoter and the first non-encoding exon of ''Raly'', a ubiquitously expressed gene in mammals.<ref name="Melmed"/> The coding exons of ''agouti'' are placed under the control of the ''Raly'' promoter, initiating ubiquitous expression of ''agouti'', increasing production of [[pheomelanin]] over [[eumelanin]] and resulting in the development of a yellow phenotype.<ref name="Tollefsbol">{{cite book |last1=Tollefsbol |first1=T. (Ed.) |title=Epigenetics in Human Disease |date=2012 |publisher=Academic Press |location=Cambridge: MA |edition=6}}</ref>
Line 37: Line 37:
==Methylation and diet intervention==
==Methylation and diet intervention==
[[File:Agouti Mice.jpg|thumb|These mice are genetically identical despite looking phenotypically different. The mouse on the left's mother was fed Bisphenol A (BPA) with a normal mouse diet and the mouse on the right's mother was fed BPA with a methyl-rich diet. The left mouse is yellow and obese, while the right mouse is brown and healthy.]]
[[File:Agouti Mice.jpg|thumb|These mice are genetically identical despite looking phenotypically different. The mouse on the left's mother was fed Bisphenol A (BPA) with a normal mouse diet and the mouse on the right's mother was fed BPA with a methyl-rich diet. The left mouse is yellow and obese, while the right mouse is brown and healthy.]]
Correct functioning of ''agouti'' requires DNA methylation. Methylation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element in the ''viable yellow'' mutation.<ref name="Spiegelman" /> When this area is unmethylated, ectopic expression of ''agouti'' occurs, and yellow phenotypes present. When the region is methylated, ''agouti'' is expressed normally, and grey phenotypes develop. 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.<ref name="Spiegelman" /> Increased methylation is correlated with increased expression of the normal ''agouti'' gene. Low levels of methylation can induce [[gene imprinting]] which results in offspring displaying consistent phenotypes to their parents, as ectopic expression of ''agouti'' is inherited through non-genomic mechanisms.<ref name="Dolinoy" /><ref name="Constância">{{cite journal | vauthors = Constância M, Pickard B, Kelsey G, Reik W | title = Imprinting mechanisms | journal = Genome Research | volume = 8 | issue = 9 | pages = 881–900 | date = September 1998 | pmid = 9750189 | doi = 10.1101/gr.8.9.881 }}</ref>
Correct functioning of ''agouti'' requires DNA methylation. Methylation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element in the ''viable yellow'' mutation.<ref name="Spiegelman" /> Methylation on a gene causes the gene to not be expressed because it will cause the [[Promoter (genetics)|promoter]] to be turned off. In utero, the mother's diet can cause methylation or demethylation. When this area is unmethylated, ectopic expression of ''agouti'' 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.<ref name="Spiegelman" /> Increased methylation is correlated with increased expression of the normal ''agouti'' gene. Low levels of methylation can induce [[gene imprinting]] which results in offspring displaying consistent phenotypes to their parents, as ectopic expression of ''agouti'' is inherited through non-genomic mechanisms.<ref name="Dolinoy" /><ref name="Constância">{{cite journal | vauthors = Constância M, Pickard B, Kelsey G, Reik W | title = Imprinting mechanisms | journal = Genome Research | volume = 8 | issue = 9 | pages = 881–900 | date = September 1998 | pmid = 9750189 | doi = 10.1101/gr.8.9.881 }}</ref>


DNA methylation is determined ''in utero'' by maternal nutrition and environmental exposure.<ref name="Spiegelman" /> Methyl is synthesized ''de 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.<ref name="Cooney">{{cite journal | vauthors = Cooney CA, Dave AA, Wolff GL | title = Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring | journal = The Journal of Nutrition | volume = 132 | issue = 8 Suppl | pages = 2393S–2400S | date = August 2002 | pmid = 12163699 | doi = 10.1093/jn/132.8.2393S }}</ref> Adequate [[zinc]] and [[vitamin B12]] are required for methyl synthesis as they act as cofactors for transferring methyl groups.<ref name="Wilson">{{cite journal | vauthors = Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS | title = Structure and function of ASP, the human homolog of the mouse agouti gene | journal = Human Molecular Genetics | volume = 4 | issue = 2 | pages = 223–30 | date = February 1995 | pmid = 7757071 | doi = 10.1093/hmg/4.2.223 }}</ref>
DNA methylation is determined ''in utero'' by maternal nutrition and environmental exposure.<ref name="Spiegelman" /> Methyl is synthesized ''de 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.<ref name="Cooney">{{cite journal | vauthors = Cooney CA, Dave AA, Wolff GL | title = Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring | journal = The Journal of Nutrition | volume = 132 | issue = 8 Suppl | pages = 2393S–2400S | date = August 2002 | pmid = 12163699 | doi = 10.1093/jn/132.8.2393S }}</ref> Adequate [[zinc]] and [[vitamin B12]] are required for methyl synthesis as they act as cofactors for transferring methyl groups.<ref name="Wilson">{{cite journal | vauthors = Wilson BD, Ollmann MM, Kang L, Stoffel M, Bell GI, Barsh GS | title = Structure and function of ASP, the human homolog of the mouse agouti gene | journal = Human Molecular Genetics | volume = 4 | issue = 2 | pages = 223–30 | date = February 1995 | pmid = 7757071 | doi = 10.1093/hmg/4.2.223 }}</ref>


When inadequate methyl is available during early embryonic development, DNA methylation cannot occur, which increases ectopic expression of ''agouti'' and results in the presentation of the ''lethal yellow'' and ''viable yellow'' phenotypes which persist into adulthood. This leads to the development of the ''yellow 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 of ''agouti'' in offspring. Diet intervention through methyl supplementation reduces imprinting at the ''agouti'' locus, as increased methyl consumption causes the IAP element to become completely methylated and ectopic expression of ''agouti'' to be reduced.<ref name="Lopez-Calderero">{{cite journal | vauthors = López-Calderero I, Sánchez Chávez E, García-Carbonero R | title = The insulin-like growth factor pathway as a target for cancer therapy | journal = Clinical & Translational Oncology | volume = 12 | issue = 5 | pages = 326–38 | date = May 2010 | pmid = 20466617 | doi = 10.1007/s12094-010-0514-8 }}</ref> This lowers the proportion of offspring that present with the yellow phenotype and increases the number offspring that resemble ''agouti'' wild type mice with grey coats.<ref name="Dolinoy" />
When inadequate methyl is available during early embryonic development, DNA methylation cannot occur, which increases ectopic expression of ''agouti'' and results in the presentation of the ''lethal yellow'' and ''viable yellow'' phenotypes which persist into adulthood. This leads to the development of the ''yellow 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 of ''agouti'' in offspring. Diet intervention through methyl supplementation reduces imprinting at the ''agouti'' locus, as increased methyl consumption causes the IAP element to become completely methylated and ectopic expression of ''agouti'' to be reduced.<ref name="Lopez-Calderero">{{cite journal | vauthors = López-Calderero I, Sánchez Chávez E, García-Carbonero R | title = The insulin-like growth factor pathway as a target for cancer therapy | journal = Clinical & Translational Oncology | volume = 12 | issue = 5 | pages = 326–38 | date = May 2010 | pmid = 20466617 | doi = 10.1007/s12094-010-0514-8 }}</ref> This lowers the proportion of offspring that present with the yellow phenotype and increases the number offspring that resemble ''agouti'' wild type mice with grey coats.<ref name="Dolinoy" />

Revision as of 06:12, 14 November 2019

Agouti-signaling protein
Identifiers
SymbolASIP
Alt. symbolsAGTIL
NCBI gene434
HGNC745
OMIM600201
RefSeqNM_001672
UniProtP42127
Other data
LocusChr. 20 q11.2-q12
Search for
StructuresSwiss-model
DomainsInterPro

The agouti gene encodes the agouti-signaling protein (ASIP), responsible for the distribution of melanin pigment in mammals.[1][2] Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment cell) produces phaeomelanin (a red to yellow pigment), or eumelanin (a brown to black pigment).[3] This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti. In other species such as horses, the agouti gene is responsible for determining which parts of the horse will be black. Horses can either have black distributed across its body or can have black only in certain locations such as the tail, ears, mane, and the lower legs.[4]

The agouti-signaling protein (ASIP) is a competitive agonist with alpha-Melanocyte-stimulating hormone (α-MSH) to bind with melanocortin 1 receptor (MC1R) proteins. Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.[5]

In mice, the wild type agouti 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.[6] The most widely studied allele variants are the lethal yellow mutation (Ay) and the viable yellow mutation (Avy) which are caused by ectopic expression of agouti.[6] These mutations are synonymous with the yellow obese syndrome which is characterized by early onset obesity, hyperinsulinemia and tumorigenesis.[6][7]

Proposed mechanism for the relationship between ectopic agouti expression and the development of yellow obese syndrome

Pigment development

The murine agouti gene locus is found on chromosome 2 and encodes a 131 amino acid protein. This protein signals the distribution of melanin pigments in epithelial melanocytes located at the base of hair follicles.[8] Expression is more sensitive on ventral hair than dorsal hair.[9] Agouti is not directly secreted in the melanocyte as it works as a paracrine factor on dermal papillae cells to inhibit release of melanocortin.[10] Melanocortin acts on follicular melanocytes to increase production of eumelanin, a melanin pigment responsible for brown and black hair. When agouti is expressed, production of phaeomelanin dominates, a melanin pigment that produces yellow or red colored hair.[11] The dominance hierarchy of pigment expression explains the evolutionary persistence of the yellow phenotype of agouti, as pheomelanin expression always dominates over eumelanin expression.[8]

Mutations

The lethal yellow mutation (Ay) was the first embryonic mutation to be characterized in mice, as homozygous lethal yellow mice (Ay/ Ay) die early in development, due to an error in trophectoderm differentiation.[8] Lethal yellow homozygotes are rare today, while lethal yellow and viable yellow heterozygotes (Ay/a and Avy/a) remain more common. In wild-type mice agouti is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in other tissues as well.[12] This ectopic expression of the agouti gene is associated with the yellow obese syndrome, characterized by early onset obesity, hyperinsulinemia and tumorigenesis.[8]

The lethal yellow (Ay) mutation is due to an upstream deletion at the start site of agouti transcription. This deletion causes the genomic sequence of agouti to be lost, except the promoter and the first non-encoding exon of Raly, a ubiquitously expressed gene in mammals.[9] The coding exons of agouti are placed under the control of the Raly promoter, initiating ubiquitous expression of agouti, increasing production of pheomelanin over eumelanin and resulting in the development of a yellow phenotype.[13]

The viable yellow (Avy) mutation is due to a change in the mRNA length of agouti, 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 of agouti transcription.[14] In the proximal end of the gene, an unknown promoter then causes agouti to be constitutionally activated, and individuals to present with phenotypes consistent with the lethal yellow mutation. Although the mechanism for the activation of the promoter controlling the viable yellow mutation is unknown, the strength of coat color has been correlated with the degree of gene methylation, which is determined by maternal diet and environmental exposure.[14] As agouti itself inhibits melanocortin receptors responsible for eumelanin production, the yellow phenotype is exacerbated in both lethal yellow and viable yellow mutations as agouti gene expression is increased. Agouti is unique because although it is a recessive allele, heterozygotes will appear yellow, not the dominant brown or black.[15]

Viable yellow (Avy/a) and lethal yellow (Ay/a) heterozygotes have shortened life spans and increased risks for developing early onset obesity, type II diabetes mellitus and various tumors.[10][16] The increased risk of developing obesity is due to the dysregulation of appetite, as agouti agonizes the agouti-related protein (AGRP), responsible for the stimulation of appetite via hypothalamic NPY/AGRP orexigenic neurons.[14] Agouti also promotes obesity by antagonizing melanocyte-stimulating hormone (MSH) at the melanocortin receptor (MC4R), as MC4R is responsible for regulating food intake by inhibiting appetite signals.[17] The increase in appetite is coupled to alterations in nutrient metabolism due to the paracrine actions of agouti on adipose tissue, increasing levels of hepatic lipogenesis, decreasing levels of lipolysis and increasing adipocyte hypertrophy.[18] This increases body mass and leads to difficulties with weight loss as metabolic pathways become dysregulated. Hyperinsulinemia is caused by mutations to agouti, as the agouti protein functions in a calcium dependent manner to increase insulin secretion in pancreatic beta cells, increasing risks of insulin resistance.[19] Increased tumor formation is due to the increased mitotic rates of agouti, which are localized to epithelial and mesenchymal tissues.[13]

Methylation and diet intervention

These mice are genetically identical despite looking phenotypically different. The mouse on the left's mother was fed Bisphenol A (BPA) with a normal mouse diet and the mouse on the right's mother was fed BPA with a methyl-rich diet. The left mouse is yellow and obese, while the right mouse is brown and healthy.

Correct functioning of agouti requires DNA methylation. Methylation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element in the viable yellow mutation.[16] Methylation on a gene causes the gene to not be expressed because it will cause the promoter to be turned off. In utero, the mother's diet can cause methylation or demethylation. When this area is unmethylated, ectopic expression of agouti 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.[16] Increased methylation is correlated with increased expression of the normal agouti gene. Low levels of methylation can induce gene imprinting which results in offspring displaying consistent phenotypes to their parents, as ectopic expression of agouti is inherited through non-genomic mechanisms.[14][20]

DNA methylation is determined in utero by maternal nutrition and environmental exposure.[16] Methyl is synthesized de 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.[21] Adequate zinc and vitamin B12 are required for methyl synthesis as they act as cofactors for transferring methyl groups.[22]

When inadequate methyl is available during early embryonic development, DNA methylation cannot occur, which increases ectopic expression of agouti and results in the presentation of the lethal yellow and viable yellow phenotypes which persist into adulthood. This leads to the development of the yellow 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 of agouti in offspring. Diet intervention through methyl supplementation reduces imprinting at the agouti locus, as increased methyl consumption causes the IAP element to become completely methylated and ectopic expression of agouti to be reduced.[23] This lowers the proportion of offspring that present with the yellow phenotype and increases the number offspring that resemble agouti wild type mice with grey coats.[14]

Human homologue

Main article: Agouti-signaling protein

Agouti signaling protein (ASP) is the human homologue of murine agouti. It is encoded by the human agouti gene on chromosome 20 and is a 132 amino acid protein. It is expressed more broadly than murine agouti, as it is found in adipose tissue, pancreas, testes and ovaries.[22] ASP has 85% similarity to the murine form of agouti.[24] As ectopic expression of murine agouti leads to the development of the yellow obese syndrome, this is expected to be consistent in humans.[24] The yellow obese syndrome increases the development of many chronic diseases, including obesity, type II diabetes mellitus and tumorigenesis.[6]

ASP has similar pharmacological activation to murine agouti, as melanocortin receptors are inhibited through competitive antagonism.[25] Inhibition of melanocortin by ASP can also be through non-competitive methods, broadening its range of effects.[13] The function of ASP differs to murine agouti. ASP effects the quality of hair pigmentation whereas murine agouti controls the distribution of pigments that determine coat color.[14] ASP has neuroendocrine functions consistent with murine agouti, as it agonizes via AgRP neurons in the hypothalamus and antagonizes MSH at MC4Rs which reduce satiety signals. As appetite signals increase and satiety signals decrease, body mass is likely to increase and individuals are more susceptible to becoming obese. The mechanism underlying hyperinsulinemia in humans is consistent with murine agouti, as insulin secretion is heightened through calcium sensitive signaling in pancreatic beta cells. The mechanism for ASP induced tumorigenesis remains unknown in humans. AgRP acts as an appetite stimulator. It works by increasing appetite and decreasing metabolism and may be linked to obesity in both humans and mice.[26] Over-expression of AgRP has been linked to obesity in males, while certain polymorphisms of AgRP are linked to eating disorders like anorexia nervosa.[27][28]

References

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  26. ^ Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (March 1997). "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development. 11 (5): 593–602. doi:10.1101/gad.11.5.593. PMID 9119224.
  27. ^ Katsuki A, Sumida Y, Gabazza EC, Murashima S, Tanaka T, Furuta M, et al. (May 2001). "Plasma levels of agouti-related protein are increased in obese men". The Journal of Clinical Endocrinology and Metabolism. 86 (5): 1921–4. doi:10.1210/jcem.86.5.7458. PMID 11344185.
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Further reading

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