Dr David Enshell-Seijffers – The Serine Protease Activity of Corin Is Required for Normal Pigment Type Switching

Dr David Enshell-Seijffers

To the Editor

The production and deposition of pigment in mouse skin are confined to the hair follicle and hair shaft, respectively. Hair pigmentation in mice involves the deposition of two types of pigment, black (eumelanin) and yellow (pheomelanin), in a very specific pattern (Barsh et al., 2000). Pigment, either black or yellow, is synthesized during the growth phase (anagen) of the hair cycle by melanocytes that reside in the hair bulb surrounding the upper half of the dermal papilla (DP), a specialized mesenchymal compartment that plays important roles in regulating different aspects of hair follicle biology. Keratinocytes in the hair bulb that undergo differentiation to form the building blocks of the hair shaft take up pigment from nearby melanocytes, leading to the formation of pigmented hair.Activity of Mc1r receptor in melanocytes results in black pigment production (Jackson et al., 2007Slominski et al., 2005Smart and Low, 2003). Binding of Agouti to Mc1r reduces Mc1r signaling and switches the production from black pigment to yellow (Ollmann et al., 1998). During early anagen, a sharp peak of Agouti expression in DP cells is observed (Millar et al., 1995). This peak generates a short and provisional period in which Mc1r activity is suppressed by Agouti and temporarily switches the melanocytes to produce pheomelanin. This creates a subapical yellow band in an otherwise black hair, resulting in an overall appearance of a mottled brown hair coat.The interaction between Mc1r and Agouti is modified by Corin (Enshell-Seijffers et al., 2008). Corin encodes a type II transmembrane serine protease that is expressed specifically in the DP and adjusts Agouti inhibition by narrowing the window of effective Agouti activity. In the absence of Corin, Agouti activity is prolonged and the yellow band is extended, leading to lighter coat color. Because Corin is a type II transmembrane serine protease and its single-pass transmembrane domain resides in close proximity to the N-terminus, most of Corin is extracellular (Figure 1a). In addition to regulating pigment type switching, Corin plays important role in blood pressure regulation. The protease activity of Corin in the heart cleaves the prohormone Nppa to its active form and thus activates the natriuretic peptide pathway to control blood tension (Chan et al., 2005Yan et al., 2000). In the uterus, Corin activates Nppa to regulate blood pressure during pregnancy by augmenting trophoblast invasion and remodeling spiral arteries, thus preventing preeclampsia (Cui et al., 2012). In contrast, little is known about the molecular mechanism by which Corin acts to inhibit Agouti activity and regulate pigment type switching.

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