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Human Molecular Genetics Advance Access published online on July 25, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm191
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Humanised MC1R Transgenic Mice Reveal Human Specific Receptor Function

Ian J. Jackson*, Peter S. Budd, Margaret Keighren and Lisa McKie

MRC Human Genetics Unit, Western General Hospital Crewe Road Edinburgh UK EH4 2XU

* Corresponding author Phone +44 131 467 8409, Fax +44 131 467 8456 ian.jackson{at}hgu.mrc.ac.uk

Received April 23, 2007; Revised July 14, 2007; Accepted July 14, 2007

The melanocortin receptor, MC1R, is a key regulator of pigmentation in mammals, and is necessary for production of dark eumelanin pigment. Human MC1R variants with reduced or absent function are associated with red hair; mouse mutants result in yellow fur. Previous reports indicate differences between mouse and human receptors in their sensitivity to, and requirement for, {alpha}MSH agonist. We have generated a transgenic mouse model in which coat pigmentation is mediated solely by human MC1R. Although the hair pigment pattern is superficially normal, we show the human receptor is more sensitive to exogenous ligand than mouse Mc1r. Furthermore, although the endogenous receptor antagonist, agouti signalling protein, blocks activation of human MC1R, its action is unlike that on the mouse receptor in that it does not generate an inverse signal. In transfected cells both receptors show ligand independent signalling. However, in transgenic mice the human receptor does not elicit significant eumelanin synthesis in absence of ligand, in contrast to the mouse receptor which gives normal eumelanogenesis without ligand. Thus the mouse model recapitulates the observation that humans mutated in POMC, the melanocortin precursor gene, lack eumelanin and have red hair. We suggest this apparent paradox can be explained by the much lower receptor number expressed in human versus mouse melanocytes, resulting in a much lower endogenous signalling in vivo.


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