Review
Pleiotropy in the melanocortin system, coloration and behavioural syndromes

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In vertebrates, melanin-based coloration is often associated with variation in physiological and behavioural traits. We propose that this association stems from pleiotropic effects of the genes regulating the synthesis of brown to black eumelanin. The most important regulators are the melanocortin 1 receptor and its ligands, the melanocortin agonists and the agouti-signalling protein antagonist. On the basis of the physiological and behavioural functions of the melanocortins, we predict five categories of traits correlated with melanin-based coloration. A review of the literature indeed reveals that, as predicted, darker wild vertebrates are more aggressive, sexually active and resistant to stress than lighter individuals. Pleiotropic effects of the melanocortins might thus account for the widespread covariance between melanin-based coloration and other phenotypic traits in vertebrates.

Section snippets

Adaptive function of melanin-based coloration

Pigmentation of the hair, skin, cuticle, feather and eye, which is mainly determined by brown to black eumelanin and yellow to reddish-brown pheomelanin, is one of the phenotypes that varies most in vertebrates (Figure 1). Melanin-based coloration is frequently implicated in social communication [1] and covaries with many other physiological, morphological and behavioural traits [2]. Whereas some traits such as antibiotic activity and resistance to solar radiation and oxidative stress can

The melanocortin system

Melanocortins are posttranslational products of the proopiomelanocortin (POMC) gene. In vertebrates, the POMC and the five MCR genes are highly conserved and their tissue distribution and functions are similar across species with few exceptions [6]. Successive cell-specific processing and posttranslational modifications of the POMC prohormone generate at least four melanocortin peptides (α-, β- and γ-MSH and ACTH) as well as endorphins [7]. In vertebrates, the principal MCR expressed in the

Pleiotropic effects of the melanocortin system

Because melanocortins bind not only to MC1R but also to MC2–5R which are responsible for several physiological and behavioural functions (Figure 3), this might result in a covariation between melanin-based coloration and other phenotypic traits. To obtain information on the expected covariations, we reviewed murine studies on constitutive and conditional knockouts of POMC (pomc1−/−), MC1R (e/e), MC2–5R (Mcr−/−) and AGRP genes (agrp−/−), as well as dominant agouti mutations (ASIP mutations, Ay/a

Melanin-based coloration and sexual behaviour

Melanocortins enhance fertility, female sexual receptivity and male sexual motivation and performance (Table 1). These effects are mediated partly by ACTH, which increases sexual steroid production through binding to MC2R in adrenal glands, and by all MSHs binding to MC4R through neurocrine pathways including the spinal cord and peripheral nerves [12] (Figure 3). In addition, melanocortins have a positive effect on the production of sexual hormones [13] (Table 1). Based on these effects, we

Melanin-based coloration, aggressiveness and exocrine gland activity

Melanocortins promote aggressiveness by inducing the production of aggression self-stimulating pheromones through binding to MC5R [14] (Table 1). Moreover, via MC5R, melanocortins enhance the secretion and excretion of exocrine glands, such as the murine preputial, Harderian, lacrimal and sebaceous glands (Table 1), which, for example, increase the hair lipid content and improve water repulsion of the fur [15]. Accordingly, darker eumelanic individuals should be more aggressive and have an

Melanin-based coloration and the hypothalamic-pituitary-adrenal stress response

One of the major regulators of the stress response is the hypothalamic-pituitary-adrenal (HPA) axis which consists of the hypothalamic corticotropin-releasing hormone, which stimulates the pituitaric ACTH and further activates the synthesis of glucocorticoids (cortisol and corticosterone) by binding to MC2R in adrenal glands [17]. An equivalent HPA axis also exists in the skin and is responsible for response to local cutaneous stress [18]. As shown in Table 1, stressors induce the HPA stress

Melanin-based coloration and immune function

Through binding to MC1R, MC3R and MC5R, melanocortins as well as the α-MSH-derived tripeptide α-MSH(11–13) reduce acute, allergic and systemic inflammation and septic shock, and also improve recovery after ischaemia [20] (Table 1). In addition, α-MSH-derived peptides have antipyretic activity through binding to MC4R [21] (Table 1). Finally, by binding to MC4R, melanocortins reduce apoptosis [22], oxidative stress and DNA damage induced by UV radiation in the skin [23] (Table 1). From this, we

Melanin-based coloration and energy homeostasis

Melanocortins (especially α- and β-MSH as well as their endogenous inverse agonist and antagonist AGRP) play a pivotal role in the central and peripheral control of energy homeostasis. In response to increased insulin and leptin inputs, melanocortins binding to neural MC3R and MC4R reduce food intake and coordinately stimulate energy expenditure by inducing the production of thyroid hormones, enhancing metabolic rate and increasing physical activity (Table 1). AGRP has the opposite effects [24]

Other pleiotropic effects of melanocortins

In addition to the phenotypic traits discussed above, melanocortins affect other traits, but in directions that are inconsistent across studies. Although for some traits the number of genetic and pharmacological studies is clearly insufficient, we nevertheless briefly report the effects of melanocortins to encourage further research in these directions.

Melanocortins affect growth (through binding to MC2–4R), sodium excretion (MC3R) and sleep in vertebrates, although we cannot readily predict

Evolutionary implications

As melanocortins bind to five MCRs located in many tissues and involved in a wide range of physiological and behavioural functions, they can account for the widespread association between melanin-based coloration and other phenotypic traits in wild vertebrates (Table 2). On the basis of the available experimental genetic and pharmacological studies (Table 1), we derived predictions on how melanin-based coloration might covary with five categories of traits including sexual behaviour,

Acknowledgements

We thank the Swiss National Science Foundation for financial support (to A.R. and L.K.), Alex N. Eberle, Nick Mundy, Karen Parker, Thierry Pedrazzini, François Pralong, Marc Robinson-Rechavi, Andrzej Slominski, Bernard Thorens, Jean-Nicolas Volff and four anonymous reviewers for helpful comments on a previous version of the manuscript.

Glossary

ACTH
Adrenocorticotropic hormone is a melanocortin which is part of the HPA axis.
Agonist
Molecule that binds to a specific receptor and triggers a response in the cell.
AGRP
Agouti-related protein is an inverse agonist and antagonist at MC3R and MC4R in the brain.
Analogue
Substance that copies one or more action of a molecule.
Antagonist
Molecule that prevents the activation of a receptor.
ASIP
Agouti-signalling protein, also referred to as Agouti or Nonagouti in mice, is an inverse agonist and

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