A β-Defensin Mutation Causes Black Coat Color in Domestic Dogs

Abstract

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 β-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 β-defensins, a protein family previously implicated in innate immunity, and identify an additional class of ligands for signaling through melanocortin receptors. AUTHORS' SUMMARYThe marked spectrum of color and diversity of patterns that we see in mammals arises, unexpectedly, from variation in the quantity, quality, and regional distribution of just two types of pigment-black eumelanin and yellow pheomelanin. The appeal of unusual coat colors and patterns has motivated their selection in domestic animals, providing geneticists with a model for studying gene action and interaction that began a century ago and continues today. Most of the work has been carried out in laboratory mice, where studies of more than 100 different coat-color mutations have provided insight into stem cell biology (hair graying), biogenesis of intracellular organelles (pigmentary dilution), and hormonereceptor interactions (switching between the synthesis of eumelanin and pheomelanin). ‡ To whom correspondence should be addressed. gbarsh@stanford.ed. * These authors contributed equally to the work. The latter process-commonly known as pigment "type-switching"-is controlled primarily by the melanocortin system, in which a family of G protein-coupled receptors (identified by virtue of their response to α-melanocyte-stimulating hormone or adrenocorticotrophic hormone) has been implicated not only in pigmentation but also in cortisol production, body weight regulation, and exocrine gland secretion. In most mammals, pigment type-switching is controlled by two genes, the Melanocortin 1 receptor (Mc1r) and Agouti, which encode a seven transmembrane-domain receptor and its extracellular ligand, respectively. Indeed, our current understanding of melanocortin biology stems from the identification in laboratory mice of Mc1r mutations as the cause of recessive yellow and Agouti mutations as the cause of lethal yellow.Clarence Cook Little, who developed many of the original laboratory mouse strains and founded The Jackson Laboratory, was also one of the first dog geneticists. He recognized that dominant inheritance of a black coat was mediated differently in dogs than in other animals (1). Using classical linkage analysis, we realized that the dominant black gene represented a previously unrecognized component of the melanocortin pathway (2). Unexpectedly, we found ...

Mapping DNA structural variation in dogs

“…Candille et al (2007) recently showed that CBD103 is the long-sought-after Dominant Black (''K'') locus in dogs. The coat color of most mammals is largely determined by the ligand-receptor pair Agouti (Ag) and Melanocortin receptor 1 (MC1R).…”

Innate Immune Defense System of the Skin

“…82 Of note, a mutation of a BD in dogs has been associated with coat colour. 83 This observation underscores the pleiotropic and sometimes unexpected functions of AMPs.…”

UV-independent induction of beta defensin 3 in neonatal human skin explants

“…In addition to MSH, MC1R signaling is regulated by other soluble ligands, most notably agouti signaling protein (ASIP) which antagonizes MC1R signaling, decreases cAMP levels, and diminishes downstream melanocyte responses such as pigment induction 3, 4 . Recently, it has become clear that β-defensin 3 (BD3), known for its role in innate antimicrobial immunity, binds and influences MC1R signaling as a neutral MC1R agonist that blunts MSH-mediated MC1R activation as well as ASP-mediated MC1R antagonism 5– 8 . Thus, BD3 may be an important regulator of MC1R-dependent melanocyte responses in the skin.…”