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Preservation of Eumelanin Hair Pigmentation in Proopiomelanocortin-Deficient Mice on a Nonagouti (a/a) Genetic Background

Department of Pathology and Laboratory Medicine (A.S., A.P.), University of Tennessee, Memphis, Tennessee 38163; Department of Biophysics (P.M.P.), Faculty of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; Vollum Institute (J.L.S., V.T., M.J.L.), Department of Behavioral Neuroscience (M.J.L.), and Center for the Study of Weight Regulation and Associated Disorders (M.J.L.), Oregon Health and Science University, Portland, Oregon 97239; and Department of Medicine (J.W.), Southern Illinois University, Springfield, Illinois 62704

Address all correspondence and requests for reprints to: Malcolm J. Low, M.D., Ph.D., Vollum Institute, L-474, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: low{at}ohsu.edu.

The original strain of proopiomelanocortin (POMC)-deficient mice (Pomc^–/–) was generated by homologous recombination in 129X1/SvJ (A^w/A^w)-derived embryonic stem cells using a targeting construct that deleted exon 3, encoding all the known functional POMC-derived peptides including MSH, from the Pomc gene. Although these Pomc^–/– mice exhibited adrenal hypoplasia and obesity similar to the syndrome of POMC deficiency in children, their agouti coat color was only subtly altered. To further investigate the mechanism of hair pigmentation in the absence of POMC peptides, we studied wild-type (Pomc^+/+), heterozygous (Pomc^+/–), and homozygous (Pomc^–/–) mice on a nonagouti (a/a) 129;B6 hybrid genetic background. All three genotypes had similar black fur pigmentation with yellow hairs behind the ears, around the nipples, and in the perianal area characteristic of inbred C57BL/6 mice. Histologic and electron paramagnetic resonance spectrometry examination demonstrated that hair follicles in back skin of Pomc^–/– mice developed with normal structure and eumelanin pigmentation; corresponding molecular analyses, however, excluded local production of MSH and ACTH because neither Pomc nor putative Pomc pseudogene mRNAs were detected in the skin. Thus, 129;B6 Pomc null mutant mice produce abundant eumelanin hair pigmentation despite their congenital absence of melanocortin ligands. These results suggest that either the mouse melanocortin receptor 1 has sufficient basal activity to trigger and sustain eumelanogenesis in vivo or that redundant nonmelanocortin pathway(s) compensate for the melanocortin deficiency. Whereas the latter implies feedback control of melanogenesis, it is also possible that the two mechanisms operate jointly in hair follicles.

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