The melanocortin 1 receptor (<i>Mc1r</i>) and prepro-opiomelanocortin (<i>Pomc</i>) are transcribed in numerous extracutaneous sites of the developing avian embryo
Creators: name: Carey, Magalie
name: Lechat, Sarah
name: Etchevers, Heather
Publisher: name: F1000Research
Year: 2016

description: Introduction: In postnatal melanocytes, the melanocortin 1 receptor Mc1r transduces signal from alpha-melanocyte stimulating hormone (a-MSH, amelanocortin), encoded by the <i>Pomc</i> gene, to induce eumelanin production and a tanning response after UV damage. Variants in human <i>MC1R</i>, previously associated with a red hair, light skin and freckling phenotype, have also been found significantly more often in an English population bearing giant forms of congenital melanocytic nevi (CMN) than in a control group without giant CMN (Kinsler et al. 2012 J Invest Dermatol 132, 2026-2032). In addition, variant alleles appear to predispose to higher birth weight in both CMN and control populations, implying an unsuspected developmental role for this signaling receptor in other tissues. We examined the expression patterns of <i>Mc1r</i> and <i>Pomc</i> transcripts in the developing chicken and compared these to that of other evolutionarily conserved markers of tissue identity to find out if Mc1r has a functional role before birth in melanocyte development. If so, might it transduce a signal involved in early melanocyte proliferation, or is Mc1r a marker of later melanocyte identity?<br><br>Results: <i>Sox10</i>+ melanoblasts, visible in the skin from embryonic day (E)4 to feather buds at E11, are in a faintly <i>Mc1r</i>- and <i>Pomc</i>-expressing basal epidermal layer, underlain by asymmetric dermal papillae expression of <i>Pomc</i>. <i>Pomc</i> in the brain and pituitary at HH31-32 (E7.5) has no equivalent alpha-MSH immunoreactivity. alpha-MSH is produced in phalangeal perichondrum and digit dermis, despite wider <i>Pomc</i> distribution. <i>Mc1r</i> is strongly and asymmetrically expressed in digital dermis. <i>Mc1r</i> and <i>Pomc</i> are expressed in complementary but also overlapping domains. For example, <i>Pomc </i>is present from approximately the third day of development in the dorsal brain and spinal cord, and hindlimb bud mesenchyme, followed by the dorsal root ganglia. Mc1r is not expressed until HH19 in the lateral mesoderm between the limb buds, and ventral myotomes. At HH29 (E6-6.5), Mc1r expression is in restricted domains of ventral limb dermis and specific arcs of the perichondral circumference that may be tendon attachment points, while hypaxial muscles of the trunk and limbs express the receptor widely. <i>Pomc </i>is complementary in some domains and overlaps in others, such as many muscle groups. It is expressed in the HH33 (E8) neural retina and brain, as well as in <i>Sox10</i>+ cranial ganglia and some <i>Mc1r</i>+ cephalic muscles and dermis.<br><br>Conclusions: <i>Mc1r </i>is broadly expressed in certain mesodermal cell types from the third day of incubation on, and <i>Pomc </i>in lineages derived from all germ layers. Other melanocortin-binding ligands derived from the Pomc propeptide may be expressed, but its highest affinity product for the Mc1r receptor, alpha-MSH, is present and the most likely endogenous ligand. Other products of Pomc are known to be potential Mc1r ligands. <i>Sox10</i>+ melanoblasts do not appear to express <i>Mc1r </i>prenatally. Pax3, a transcriptional co-regulator with Sox10 of the master pigment cell identity gene <i>Mitf</i>, is expressed in certain <i>Pomc </i>and <i>Mc1r</i>-expressing tissues. Known roles for Pax3 in central nervous system and muscle specification imply a testable hypothesis: that Pax3 may also regulate Pomc or Mc1r transcription. Mc1r could be repressed by Sox10 (Lee et al. 2012 J Cell Biol 198, 799-813). Endocrine signaling to Mc1r-expressing hypaxial myotome and muscle is unexpected, as is the  co-expression of ligand and receptor during fetal skin development in the chick. No Mc1r in melanoblasts implies that evolutionary co-option of the signaling pathway occurred for separate use in prenatal tissues and peri- or postnatal melanocytes. The dynamic embryonic expression of manganese superoxide dismutase in many overlapping areas with <i>Pomc</i> and <i>Mc1r</i> (Yon et al. 2012 Int J Dev Biol 55, 327-334) may indicate a response to endogenous reactive oxygen species before exposure to UV light.<br><br>We have identified the melanocortin-1 signaling pathway as a new potential influence on the growth of bone and muscle as well as skin during prenatal development.