title: Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation.
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.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Anders R
authors.initials: AR
authors.lastname: Hellström
authors.forename: Brenda
authors.initials: B
authors.lastname: Watt
authors.forename: Shahrzad Shirazi
authors.initials: SS
authors.lastname: Fard
authors.forename: Danièle
authors.initials: D
authors.lastname: Tenza
authors.forename: Paula
authors.initials: P
authors.lastname: Mannström
authors.forename: Kristina
authors.initials: K
authors.lastname: Narfström
authors.forename: Björn
authors.initials: B
authors.lastname: Ekesten
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.forename: Jimmy
authors.initials: J
authors.lastname: Larsson
authors.forename: Mats
authors.initials: M
authors.lastname: Ulfendahl
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.forename: Susanne
authors.initials: S
authors.lastname: Kerje
authors.forename: Finn
authors.initials: F
authors.lastname: Hallböök
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D006200:Hair Color / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009154:Mutation; D010088:Oxidoreductases / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D012867:Skin / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008543:Melanins; D008562:Membrane Glycoproteins; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen; C041877:eumelanin; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse