Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin‐1 receptor in the grey squirrel (<i>Sciurus carolinensis</i>)

McRobie, Helen R.; King, Linda M.; Fanutti, Cristina; Symmons, Martyn F.; Coussons, Peter J.

doi:10.1016/j.febslet.2014.05.032

Cited by 14 publications

(11 citation statements)

References 56 publications

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“…In an Agouti-null context, MC1R is hyper-activated by its active ligand, the pituitary melanocortin hormone α-MSH, which triggers a melanocyte regulatory cascade that culminates with eumelanin production. It has been proposed that wild-type Agouti can become an agonist of MC1R melanic variants (McRobie et al 2014), suggesting that certain gain-of-function MC1R alleles reverse the responsiveness of the receptor to the Agouti ligand itself. In addition to Agouti, the β-defensin 3/CBD103 peptide is secreted by skin epithelia, strongly binds to MC1R, and was shown to be responsible for melanism in dogs (Candille et al 2007).…”

Section: A Few Select Genes For Body-wide Switches In Melanin Productmentioning

confidence: 99%

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Martin

Courtier‐Orgogozo

2017

Diversity and Evolution of Butterfly Wing Patterns

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What types of genetic changes underlie evolution? Secreted signaling molecules (syn. ligands) can induce cells to switch states and thus largely contribute to the emergence of complex forms in multicellular organisms. It has been proposed that morphological evolution should preferentially involve changes in developmental toolkit genes such as signaling pathway components or transcription factors. However, this hypothesis has never been formally confronted to the bulk of accumulated experimental evidence. Here we examine the importance of ligandcoding genes for morphological evolution in animals. We use Gephebase (http:// www.gephebase.org), a database of genotype-phenotype relationships for evolutionary changes, and survey the genetic studies that mapped signaling genes as causative loci of morphological variation. To date, 19 signaling genes represent 20% of the cases where an animal morphological change has been mapped to a gene (80/391). This includes the signaling gene Agouti, which harbors multiple cis-regulatory alleles linked to color variation in vertebrates, contrasting with the effects of coding variation in its target, the melanocortin receptor MC1R. In sticklebacks, genetic mapping approaches have identified 4 signaling genes out of 14 loci associated with lake adaptations. Finally, in butterflies, a total of 18 allelic variants of the WntA Wnt-family ligand cause color pattern adaptations related to wing mimicry, both within and between species. We discuss possible hypotheses explaining these cases of natural replication (genetic parallelism) and conclude that signaling ligand loci are an important source of sequence variation underlying morphological change in nature.

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Section: A Few Select Genes For Body-wide Switches In Melanin Productmentioning

confidence: 99%

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Martin

Courtier‐Orgogozo

2017

Diversity and Evolution of Butterfly Wing Patterns

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“…Unique to this GPCR family is the presence of endogenous antagonists, agouti (ASP) and agouti-related protein (AGRP) [16-18]. Additionally, AGRP has been demonstrated to possess inverse agonist activity (directly decreasing cAMP levels within a cell) at the MC4R in mice and humans [19, 20], while agouti has been shown to be an inverse agonist in cells expressing the grey squirrel MC1R [21]. …”

Section: Introductionmentioning

confidence: 99%

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress.

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“…These pathways include baseline hypothalamic-pituitary-adrenal (HPA) physiology, HPA axis reactivity to stressors, and the immune system [89][90][91][92][93]-each of which is a dimension of host physiology known to affect wildlife microbiomes [29,37,94]. In eastern grey squirrels, the melanism-causing MC1R mutation [95] has been connected to behavioural and physiological differences [96,97], most notably thermogenic physiology [39,40]. Speci cally, melanic squirrels show greater plasticity in their ability to adaptively lower their basal metabolic rate when exposed to sub-zero ambient temperatures.…”

Section: Discussionmentioning

confidence: 99%

Shades of Grey: Host Phenotype Dependent Effect of Urbanization on the Bacterial Microbiome of a Wild Mammal

Stothart

Newman

2021

Preprint

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Background Host-associated microbiota are integral to the ecology of their host and may help wildlife species cope with rapid environmental change. Urbanization is a globally replicated form of severe environmental change which we can leverage to better understand wildlife microbiomes. Does the colonization of separate cities result in parallel changes in the intestinal microbiome of wildlife, and if so, does within-city habitat heterogeneity matter? Using 16S rRNA gene amplicon sequencing, we quantified the effect of urbanization on the microbiome of eastern grey squirrels (Sciurus carolinensis). Eastern grey squirrels are ubiquitous in rural and urban environments throughout their native range, across which they display an apparent coat colour polymorphism (agouti, black, intermediate). Results Grey squirrel microbiomes differed between rural and city environments; however, comparable variation was explained by habitat heterogeneity within cities. Our analyses suggest that operational taxonomic unit (OTU) community structure was more strongly influenced by local environmental conditions (rural and city forests versus human built habitats) than urbanization of the broader landscape (city versus rural). The bacterial genera characterizing the microbiomes of built-environment squirrels are thought to specialize on host-derived products and have been linked in previous research to low fibre diets. However, despite an effect of urbanization at fine spatial scales, phylogenetic patterns in the microbiome were coat colour phenotype dependent. City and built environment agouti squirrels displayed greater phylogenetic beta-dispersion than those in rural or forest environments, and null modelling results indicated that the phylogenetic structure of urban agouti squirrels did not differ greatly from stochastic expectations. Conclusions Habitat heterogeneity at fine spatial scales affects host-associated microbiomes, however, we found little evidence that this pattern was the result of similar selective pressures acting on the microbiome within environments. Further, this result, those of phylogeny-independent analyses, and patterns of beta-dispersion lead us to suggest that microbiota dispersal and ecological drift are integral to shaping the inter-environmental differences we observed. These patterns were partly mediated by squirrel coat colour phenotype. Given a well-known urban cline in squirrel coat colour melanism, grey squirrels provide a useful free-living system with which to study how host genetics mediate environment x microbiome interactions.

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Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin‐1 receptor in the grey squirrel (Sciurus carolinensis)

Cited by 14 publications

References 56 publications

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Morphological Evolution Repeatedly Caused by Mutations in Signaling Ligand Genes

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Shades of Grey: Host Phenotype Dependent Effect of Urbanization on the Bacterial Microbiome of a Wild Mammal

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