The A y allele at the agouti locus enhances sensitivity to endotoxin-induced lethality in mice.
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In the course of investigations on anorexia during infection, I found that B6-A(y) mice had significantly increased sensitivity to lipopolysaccharide (LPS)-induced lethality as compared with isogenic B6 mice. I also found that the sensitivity to the lethal effect of LPS dramatically increased in aged mice (age effect), both B6 and B6-A(y). However, the A(y) effect of enhancing sensitivity to LPS-induced lethality was still significant, suggesting that the A(y) effect is independent of age. In the absence of tumor necrosis factor alpha (TNFalpha), the A(y) effect was still significant, suggesting that the A(y) effect is independent of TNFalpha toxicity. A dose of LPS of 100 mug per mouse caused 15% lethality in B6, 65% in B6-A(y) (significantly higher than B6), and 100 % in leptin-deficient B6-ob/ob (significantly higher than B6 and B6-A(y)). The results support the hypothesis that endogenous leptin has a protective role against infection, and that a part of this leptin effect is mediated by alpha-melanocyte-stimulating hormone (alphaMSH). In contrast to the results of simple blockade at the melanocortin 4 receptor (MC4R), B6-A(y) suffered more severe LPS-induced anorexia than did B6; therefore, the pathway involving MC4R is not absolutely required for the LPS-induced anorexia, and the presence of pathways involving other melanocortin receptor types was suggested. Because alphaMSH is suggested to be an endogenous anti-inflammatory peptide, and because melanocortin 1 receptor (MC1R) is expressed in various cutaneous cell types, the A(y) effect might be caused via the pathway involving MC1R. Physiologic significance of alphaMSH-MC1R interaction in host defense against infection is discussed. (+info)
A -defensin mutation causes black coat color in domestic dogs.
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Genetic analysis of mammalian color variation has provided fundamental insight into human biology and disease. In most vertebrates, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls pigment type-switching, but in domestic dogs, a third gene is implicated, the K locus, whose genetic characteristics predict a previously unrecognized component of the melanocortin pathway. We identify the K locus as beta-defensin 103 (CBD103) and show that its protein product binds with high affinity to the Mc1r and has a simple and strong effect on pigment type-switching in domestic dogs and transgenic mice. These results expand the functional role of beta-defensins, a protein family previously implicated in innate immunity, and identify an additional class of ligands for signaling through melanocortin receptors. (+info)
Chemical disulfide mapping identifies an inhibitor cystine knot in the agouti signaling protein.
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The agouti signaling protein (ASIP) and its homolog, the agouti-related protein (AgRP), act as inverse agonists that control, respectively, pigmentation and metabolic function in mammals. NMR investigations find that the C-terminal domains of these proteins adopt a fold consistent with an inhibitor cystine knot (ICK), previously identified in invertebrate toxins. Although these structural studies suggest that ASIP and AgRP define a new mammalian protein fold class, the results with ASIP are inconclusive. Here, we apply direct chemical mapping to determine the complete set of disulfide linkages in ASIP. The results demonstrate unequivocally that ASIP adopts the ICK fold and thereby supports a recent evolution structure function analysis, which proposes that ASIP and AgRP arose from a common antagonist ligand. (+info)
The serine protease Corin is a novel modifier of the Agouti pathway.
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The hair follicle is a model system for studying epithelial-mesenchymal interactions during organogenesis. Although analysis of the epithelial contribution to these interactions has progressed rapidly, the lack of tools to manipulate gene expression in the mesenchymal component, the dermal papilla, has hampered progress towards understanding the contribution of these cells. In this work, Corin was identified in a screen to detect genes specifically expressed in the dermal papilla. It is expressed in the dermal papilla of all pelage hair follicle types from the earliest stages of their formation, but is not expressed elsewhere in the skin. Mutation of the Corin gene reveals that it is not required for morphogenesis of the hair follicle. However, analysis of the ;dirty blonde' phenotype of these mice reveals that the transmembrane protease encoded by Corin plays a critical role in specifying coat color and acts downstream of agouti gene expression as a suppressor of the agouti pathway. (+info)
Recessive black is allelic to the yellow plumage locus in Japanese quail and associated with a frameshift deletion in the ASIP gene.
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Interactions between SNP alleles at multiple loci contribute to skin color differences between caucasoid and mongoloid subjects.
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This study aimed to identify single nucleotide polymorphism (SNP) alleles at multiple loci associated with racial differences in skin color using SNP genotyping. A total of 122 Caucasians in Toledo, Ohio and 100 Mongoloids in Japan were genotyped for 20 SNPs in 7 candidate genes, encoding the Agouti signaling protein (ASIP), tyrosinase-related protein 1 (TYRP1), tyrosinase (TYR), melanocortin 1 receptor (MC1R), oculocutaneous albinism II (OCA2), microphthalmia-associated transcription factor (MITF), and myosin VA (MYO5A). Data were used to analyze associations between the 20 SNP alleles using linkage disequilibrium (LD). Combinations of SNP alleles were jointly tested under LD for associations with racial groups by performing a chi(2) test for independence. Results showed that SNP alleles at multiple loci can be considered the haplotype that contributes to significant differences between the two population groups and suggest a high probability of LD. Confirmation of these findings requires further study with other ethnic groups to analyze the associations between SNP alleles at multiple loci and skin color variation among races. (+info)