Agouti Gene

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Richard P. Woychik - One of the best experts on this subject based on the ideXlab platform.

  • Liver-specific expression of the Agouti Gene in transgenic mice promotes liver carcinoGenesis in the absence of obesity and diabetes
    Molecular cancer, 2004
    Co-Authors: Alexander Kuklin, R. L. Mynatt, Mitchell L. Klebig, William O. Wilkison, Richard P. Woychik, Laura L. Kiefer, Edward J Michaud
    Abstract:

    Background The Agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse Agouti Gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinoGenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the Agouti Gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we Generated lines of transgenic mice expressing high levels of Agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the Agouti transGene in the liver were quantified by Northern blot analysis. Functional Agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the α-melanocyte stimulating hormone (αMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded.

  • The Role of the Agouti Gene in the Yellow Obese Syndrome
    Journal of Nutrition, 1997
    Co-Authors: R. J. Miltenberger, R. L. Mynatt, John E. Wilkinson, Richard P. Woychik
    Abstract:

    The yellow obese syndrome in mice encompasses many pleiotropic effects including yellow fur, maturity-onset obesity, hyperinsulinemia, insulin resistance, hyperglycemia, increased skeletal length and lean body mass, and increased susceptibility to neoplasia. The molecular basis of this syndrome is beginning to be unraveled and may have implications for human obesity and diabetes. Normally, the Agouti Gene is expressed during the hair-growth cycle in the neonatal skin where it functions as a paracrine regulator of pigmentation. The secreted Agouti protein antagonizes the binding of the alpha-melanocyte-stimulating hormone to its receptor (melanocortin 1 receptor) on the surface of hair bulb melanocytes, causing alterations in intracellular cAMP levels. Widespread, ectopic expression of the mouse Agouti Gene is central to the yellow obese phenotype, as demonstrated by the molecular cloning of several dominant Agouti mutations and the ubiquitous expression of the wild-type Agouti Gene in transgenic mice. Recent experiments have revealed that the hypothalamus and adipose tissue are biologically active target sites for Agouti in the yellow obese mutant lines.

  • Combined effects of insulin treatment and adipose tissue-specific Agouti expression on the development of obesity
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: R. L. Mynatt, Michael B. Zemel, R. J. Miltenberger, Mitchell L. Klebig, John E. Wilkinson, William O. Wilkison, Richard P. Woychik
    Abstract:

    The Agouti Gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the Agouti locus in mice cause the ectopic, ubiquitous expression of Agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human Agouti protein is 85% homologous to mouse Agouti; however, unlike the mouse Agouti Gene, human Agouti is normally expressed in adipose tissue. To address whether expression of Agouti in human adipose tissue is physiologically relevant, transgenic mice were Generated that express Agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing Agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that Agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of Agouti’s role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

  • the effects of calcium channel blockade on Agouti induced obesity
    The FASEB Journal, 1996
    Co-Authors: Jung Han Kim, R. L. Mynatt, Richard P. Woychik, Jerry W. Moore, Naima Moustaid, Michael B. Zemel
    Abstract:

    We have previously observed that obese viable yellow (Avy/a) mice exhibit increased intracellular Ca2+ ([Ca2+]i) and fatty acid synthase (FAS) Gene expression; further, recombinant Agouti protein increases in cultured adipocytes and these effects are inhibited by Ca2+ channel blockade. Accordingly, we determined the effect of Ca2+ channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the Agouti Gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5+/-0.6 vs. 27.3+/-0.3 g; P<0.001) and exhibited a 0.81 degrees C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensit...

  • upregulation of adipocyte metabolism by Agouti protein possible paracrine actions in yellow mouse obesity
    American Journal of Physiology-endocrinology and Metabolism, 1996
    Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. Moustaid
    Abstract:

    Mutations leading to ectopic expression of the murine Agouti Gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s...

Gregory S. Barsh - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of the dog Agouti Gene and a nonAgoutimutation in German Shepherd Dogs
    Mammalian Genome, 2004
    Co-Authors: Julie A. Kerns, J. Newton, Tom G. Berryere, Edward M. Rubin, Jan-fang Cheng, Sheila M. Schmutz, Gregory S. Barsh
    Abstract:

    The interaction between two Genes, Agouti and Melanocortin-1 receptor ( Mc1r ), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs ( Canis familiaris ), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular Genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti Gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.

  • characterization of the dog Agouti Gene and a nonAgouti mutation in german shepherd dogs
    Mammalian Genome, 2004
    Co-Authors: Julie A. Kerns, Tom G. Berryere, Edward M. Rubin, Jan-fang Cheng, Sheila M. Schmutz, J M Newton, Gregory S. Barsh
    Abstract:

    The interaction between two Genes, Agouti and Melanocortin-1 receptor (Mc1r), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs (Canis familiaris), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular Genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti Gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.

  • Differential spontaneous transformation in vitro of newly established mouse fibroblast lines carrying or lacking the viable yellow mutation (Avy) of the mouse Agouti locus.
    Molecular carcinogenesis, 1996
    Co-Authors: Wen-luang Wendy Hsiao, Michael Martin Ollmann, Gregory S. Barsh, George L. Wolff, Beverly M. North, Hung Fan
    Abstract:

    The pleiotropic effects of the viable yellow mutation (Avy), an allele of the mouse Agouti coat-color locus, include increased susceptibility to spontaneous and chemically induced tumors that affect a wide variety of tissues. As a first step toward understanding the molecular basis of this phenomenon, we established permanent fibroblast-like cell lines from newborn Avy/a and control congenic a/a mice and compared their growth characteristics in vitro. From the VY/WffC3Hf/Nctr and YS/WffCH3f/Nctr-Avy inbre strains, each of which carries the Avy allele on a congenic background, 38 clonal Avy/a and 16 clonal a/a lines were established. Regardless of inbred strain, all Avy/a cell lines exhibited a significant degree of spontaneous transformation, as assessed by focus formation in monolayer culture, whereas none of the a/a cell lines formed foci in prolonged cultures. To test whether changes in dosage of the Avy- or a-bearing chromosomes were related to these events, we analyzed each cell line with a closely linked molecular probe from the Emv-15 locus, which in the VY strain detects a restriction fragment length variant (RFLV) informative for the Avy- and a-bearing chromosomes. Most of the transformed foci maintained heterozygosity for RFLVs detected by the probe, but two of the transformants lost the a-associated RFLV, and at least one of the transformants exhibited amplification of the Avy-associated RFLV. When the transformants were analyzed with 5' sequences derived from the recently cloned Agouti Gene, three of eight transformants lost the a-associated RFLV, and two of the transformants showed amplification of the Avy-associated RFLV. Reverse transcriptase-polymerase chain reaction assays indicated that Agouti RNA was detected in Avy/a, not a/a cell lines. Surprisingly, some of the Avy/a transformants lacked Agouti RNA. These results suggest that deregulated expression of the Avy allele is required for the initiation but not for the maintenance of transformation of the Avy/a cell cultures. These cell lines may provide an in vitro culture system for studying the effect of the Agouti Gene on tumorigenicity as well as to potentially study other pleiotropic phenotypes.

  • expression and transgenic studies of the mouse Agouti Gene provide insight into the mechanisms by which mammalian coat color patterns are Generated
    Development, 1995
    Co-Authors: Sarah E Millar, Miles W Miller, Mary E Stevens, Gregory S. Barsh
    Abstract:

    Expression of the Agouti Gene from two different promoters, one active at the midpoint of the hair cycle and the other specific for the ventrum, is responsible for Generating a range of mammalian pigmentation patterns. We demonstrate that in postnatal mice transcripts from both promoters are confined to the dermal papilla of hair follicles, as predicted by classical transplantation experiments. Transcripts from the hair cycle promoter are detected in the embryonic whisker plate but not in other regions of the body before birth, whereas ventral-specific transcripts are detected in the ventral trunk of the embryo as well as ventral whisker plate. To investigate further the embryonic origins of adult pigmentation patterns, we carried out a detailed analysis of Agouti expression in the embryo. The ventral-specific Agouti isoform is first expressed at E10.5 in neural crest-derived ventral cells of the second branchial arch, in anterior regions of the forelimb buds and in a narrow stripe of ventral mesenchyme. By E14.5 a continuous layer of expression is observed in the upper cells of the dermis, including cells of the developing dermal papillae, and covering the entire ventral surface of the head and trunk and dorsal surfaces of the distal forelimb and hindlimb. This expression pattern reflects the domain of yellow coloration evident in adult animals and suggests that the Agouti Gene is regulated in part by factors responsible for establishing differences between the dorsal and ventral surfaces of the body during embryoGenesis. To test the hypothesis that Agouti is a paracrine signaling molecule that can influence pigment production by hair follicle melanocytes when expressed by either dermis or epidermis, as suggested by recombination and transplantation experiments, we created transgenic animals in which Agouti is expressed in basal cells of the epidermis. These animals display stripes of yellow hairs corresponding to regions of epidermal Agouti expression, confirming that Agouti signals melanocytes to synthesize yellow pigment and providing direct evidence that it functions in a paracrine manner with a restricted radius of action.

  • Structure and function of ASP, the human homolog of the mouse Agouti Gene
    Human Molecular Genetics, 1995
    Co-Authors: Brent D Wilson, Michael Martin Ollmann, Lana Kang, Markus Stoffel, Graeme I. Bell, Gregory S. Barsh
    Abstract:

    The mouse Agouti coat color Gene encodes a novel paracrine signaling molecule whose pulsatile expression 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. Utilizing linkage groups conserved between mice and humans, we have 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. 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, and expression of ASP in cell culture blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melanoma cells. The localization of ASP relative to other loci on chromosome 20 excludes it as a candidate for the MODY1 locus, a Gene responsible for one form of early-onset non-insulin-dependent diabetes mellitus or maturity-onset diabetes of the young. 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.

Edward J Michaud - One of the best experts on this subject based on the ideXlab platform.

  • Liver-specific expression of the Agouti Gene in transgenic mice promotes liver carcinoGenesis in the absence of obesity and diabetes
    Molecular cancer, 2004
    Co-Authors: Alexander Kuklin, R. L. Mynatt, Mitchell L. Klebig, William O. Wilkison, Richard P. Woychik, Laura L. Kiefer, Edward J Michaud
    Abstract:

    Background The Agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse Agouti Gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinoGenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the Agouti Gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we Generated lines of transgenic mice expressing high levels of Agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the Agouti transGene in the liver were quantified by Northern blot analysis. Functional Agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the α-melanocyte stimulating hormone (αMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded.

  • upregulation of adipocyte metabolism by Agouti protein possible paracrine actions in yellow mouse obesity
    American Journal of Physiology-endocrinology and Metabolism, 1996
    Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. Moustaid
    Abstract:

    Mutations leading to ectopic expression of the murine Agouti Gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s...

  • Upregulation of adipocyte metabolism by Agouti protein: possible paracrine actions in yellow mouse obesity
    American Journal of Physiology-Endocrinology and Metabolism, 1996
    Co-Authors: Brynn H Jones, Michael B. Zemel, William O. Wilkison, Richard P. Woychik, Edward J Michaud, Jung Han Kim, N. Moustaid
    Abstract:

    Mutations leading to ectopic expression of the murine Agouti Gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these Genes in this model could be due to direct effects of the Agouti Gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant Agouti protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in Agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the Agouti protein can directly increase lipoGenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.

  • Agouti regulation of intracellular calcium role in the insulin resistance of viable yellow mice
    Proceedings of the National Academy of Sciences of the United States of America, 1995
    Co-Authors: Michael B. Zemel, Richard P. Woychik, I R Patel, Sue H Kadwell, Edward J Michaud, Jung Han Kim, William O. Wilkison
    Abstract:

    Abstract Several dominant mutations at the Agouti locus in the mouse cause a syndrome of marked obesity, hyperinsulinemia, and insulin resistance. Although it is known that the Agouti Gene is expressed in an ectopic manner in these mutants, the precise mechanism by which the Agouti Gene product mediates these effects is unclear. Since intracellular Ca2+ is believed to play a role in mediating insulin action and dysregulation of Ca2+ flux is observed in diabetic animals and humans, we examined the status of intracellular Ca2+ in mice carrying the dominant Agouti allele, viable yellow (Avy). We show here that in mice carrying this mutation, the intracellular free calcium concentration ([Ca2+]i) is elevated in skeletal muscle, and the degree of elevation is closely correlated with the degree to which the mutant traits are expressed in individual animals. Moreover, we demonstrate that the Agouti Gene product is capable of inducing increased [Ca2+]i in cultured and freshly isolated skeletal muscle myocytes from wild-type mice. Based on these findings, we present a model in which we propose that the Agouti polypeptide promotes insulin resistance in mutant animals through its ability to increase [Ca2+]i.

  • differential expression of a new dominant Agouti allele aiapy is correlated with methylation state and is influenced by parental lineage
    Genes & Development, 1994
    Co-Authors: Edward J Michaud, Scott J. Bultman, M J Van Vugt, H O Sweet, M T Davisson, Richard P. Woychik
    Abstract:

    The Agouti Gene normally confers the wild-type coat color of mice. Dominant mutations at the Agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the Agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the Gene. This mutation, which we have named Aiapy, results in the ectopic expression of the Agouti Gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoAgouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express Agouti mRNA at high levels and exhibit marked obesity, whereas pseudoAgouti mice express Agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the Agouti locus, it is the ubiquitous expression of the wild-type Agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumoriGenesis.

William O. Wilkison - One of the best experts on this subject based on the ideXlab platform.

George L. Wolff - One of the best experts on this subject based on the ideXlab platform.

  • Maternal methyl supplements in mice affect epiGenetic variation and DNA methylation of offspring.
    The Journal of nutrition, 2002
    Co-Authors: Craig A Cooney, Apurva A Dave, George L. Wolff
    Abstract:

    This study was designed to determine if maternal dietary methyl supplements increase DNA methylation and methylation-dependent epiGenetic phenotypes in mammalian offspring. Female mice of two strains were fed two levels of dietary methyl supplement or control diet prior to and during pregnancy. Offspring of these mice vary in phenotype, which is epiGenetically determined and affects health and 2-y survival. Phenotype and DNA methylation of a long terminal repeat (LTR) controlling expression of the Agouti Gene were assayed in the resulting offspring. Methyl supplements increase the level of DNA methylation in the Agouti LTR and change the phenotype of offspring in the healthy, longer-lived direction. This shows that methyl supplements have strong effects on DNA methylation and phenotype and are likely to affect long-term health. Optimum dietary supplements for the health and longevity of offspring should be intensively investigated. This should lead to public policy guidance that teaches optimal, rather than minimal, dose levels of maternal supplements.

  • Physiological consequences of ectopic Agouti Gene expression: the yellow obese mouse syndrome
    Physiological genomics, 1999
    Co-Authors: George L. Wolff, Dean W. Roberts, Kathleen G. Mountjoy
    Abstract:

    Wolff, George L., Dean W. Roberts, and Kathleen G. Mountjoy. Physiological consequences of ectopic Agouti Gene expression: the yellow obese mouse syndrome. Physiol. Genomics 1: 151–163, 1999.—This ...

  • maternal epiGenetics and methyl supplements affect Agouti Gene expression in avy a mice
    The FASEB Journal, 1998
    Co-Authors: George L. Wolff, Ralph L Kodell, Stephen R Moore, Craig A Cooney
    Abstract:

    'Viable yellow' (Avy/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epiGenetic mosaics ranging from a yellow phenotype with maximum ectopic Agouti overexpression, through a continuum of mottled Agouti/yellow phenotypes with partial Agouti overexpression, to a pseudoAgouti phenotype with minimal ectopic expression. PseudoAgouti Avy/a mice are lean, healthy, and longer lived than their yellow siblings. Here we report that feeding pregnant black a/a dams methyl-supplemented diets alters epiGenetic regulation of Agouti expression in their offspring, as indicated by increased Agouti/black mottling in the direction of the pseudoAgouti phenotype. We also present confirmatory evidence that epiGenetic phenotypes are maternally heritable. Thus Avy expression, already known to be modulated by imprinting, strain-specific modification, and maternal epiGenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epiGenetic mechanisms, especially DNA methylation, in developing embryos.

  • Maternal epiGenetics and methyl supplements affect Agouti Gene expression in Avy/a mice
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1998
    Co-Authors: George L. Wolff, Ralph L Kodell, Stephen R Moore, Craig A Cooney
    Abstract:

    'Viable yellow' (Avy/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epiGenetic mosaics ranging from a yellow phenotype with maximum ectopic Agouti overexpression, through a continuum of mottled Agouti/yellow phenotypes with partial Agouti overexpression, to a pseudoAgouti phenotype with minimal ectopic expression. PseudoAgouti Avy/a mice are lean, healthy, and longer lived than their yellow siblings. Here we report that feeding pregnant black a/a dams methyl-supplemented diets alters epiGenetic regulation of Agouti expression in their offspring, as indicated by increased Agouti/black mottling in the direction of the pseudoAgouti phenotype. We also present confirmatory evidence that epiGenetic phenotypes are maternally heritable. Thus Avy expression, already known to be modulated by imprinting, strain-specific modification, and maternal epiGenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epiGenetic mechanisms, especially DNA methylation, in developing embryos.

  • Differential spontaneous transformation in vitro of newly established mouse fibroblast lines carrying or lacking the viable yellow mutation (Avy) of the mouse Agouti locus.
    Molecular carcinogenesis, 1996
    Co-Authors: Wen-luang Wendy Hsiao, Michael Martin Ollmann, Gregory S. Barsh, George L. Wolff, Beverly M. North, Hung Fan
    Abstract:

    The pleiotropic effects of the viable yellow mutation (Avy), an allele of the mouse Agouti coat-color locus, include increased susceptibility to spontaneous and chemically induced tumors that affect a wide variety of tissues. As a first step toward understanding the molecular basis of this phenomenon, we established permanent fibroblast-like cell lines from newborn Avy/a and control congenic a/a mice and compared their growth characteristics in vitro. From the VY/WffC3Hf/Nctr and YS/WffCH3f/Nctr-Avy inbre strains, each of which carries the Avy allele on a congenic background, 38 clonal Avy/a and 16 clonal a/a lines were established. Regardless of inbred strain, all Avy/a cell lines exhibited a significant degree of spontaneous transformation, as assessed by focus formation in monolayer culture, whereas none of the a/a cell lines formed foci in prolonged cultures. To test whether changes in dosage of the Avy- or a-bearing chromosomes were related to these events, we analyzed each cell line with a closely linked molecular probe from the Emv-15 locus, which in the VY strain detects a restriction fragment length variant (RFLV) informative for the Avy- and a-bearing chromosomes. Most of the transformed foci maintained heterozygosity for RFLVs detected by the probe, but two of the transformants lost the a-associated RFLV, and at least one of the transformants exhibited amplification of the Avy-associated RFLV. When the transformants were analyzed with 5' sequences derived from the recently cloned Agouti Gene, three of eight transformants lost the a-associated RFLV, and two of the transformants showed amplification of the Avy-associated RFLV. Reverse transcriptase-polymerase chain reaction assays indicated that Agouti RNA was detected in Avy/a, not a/a cell lines. Surprisingly, some of the Avy/a transformants lacked Agouti RNA. These results suggest that deregulated expression of the Avy allele is required for the initiation but not for the maintenance of transformation of the Avy/a cell cultures. These cell lines may provide an in vitro culture system for studying the effect of the Agouti Gene on tumorigenicity as well as to potentially study other pleiotropic phenotypes.