Abstract
PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel −/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel −/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.
Highlights
Vertebrates produce two types of pigment - red/yellow pheomelanins and black/brown eumelanins [1]
Mutations in PMEL underlie some spectacular color phenotypes in animals including Dominant white color in chickens, Silver in horses, and Merle in dogs, but no spontaneous mutation causing a complete inactivation of this gene has yet been found in mammals
We have developed a PMEL knockout mouse to further study the function of this protein
Summary
Vertebrates produce two types of pigment - red/yellow pheomelanins and black/brown eumelanins [1]. PMEL expression starts at E9.5 in the presumptive retinal pigment epithelium (RPE) and at E10.5 in neural crest-derived melanoblasts, suggesting a function in the early stages of melanosome biogenesis [3]. Several studies have shown that fragments derived from proteolytic maturation of PMEL form the fibrillar matrix within melanosomes upon which eumelanins are deposited [4]. A role for PMEL fibrils in melanosome maturation is suggested by their ability to template and accelerate polymerization of highly reactive eumelanin precursors [5,6,7]. The presence of PMEL has been assumed to be critical for the normal production or stabilization of eumelanin but not pheomelanin. Fibrils formed by PMEL in vitro have biophysical hallmarks of amyloid such as those formed in Alzheimer’s and Parkinson’s diseases [6], providing a model for functional/nonpathological amyloid formation [8]
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