Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation.
Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation.
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DOI：
10.1371/journal.pgen.1002285
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Andersson L
中科院分区：
文献类型：
--
作者：
Hellström AR;Watt B;Fard SS;Tenza D;Mannström P;Narfström K;Ekesten B;Ito S;Wakamatsu K;Larsson J;Ulfendahl M;Kullander K;Raposo G;Kerje S;Hallböök F;Marks MS;Andersson L
PMEL是一种淀粉样蛋白，似乎仅在色素细胞中表达，并在早期黑素体内形成腔内原纤维，在后期真黑素存款在其上。PMEL在脊椎动物中是很保守的，几个物种中的等位基因变体与表皮组织中真黑素水平的降低有关。然而，在大多数这些情况下，不清楚等位基因变体是否反映功能获得或功能丧失，并且在哺乳动物中没有完全的PMEL功能丧失的报道。在这里，我们已经创建了一个小鼠品系，其中Pmel基因已经失活（Pmel −/−）。这些小鼠是完全可行的，可生育的，并且没有表现出明显的发育缺陷。Pmel −/−黑素细胞内的黑素体是球形的，与野生型动物中存在的椭圆形形成对比。这一特点被记录在原代培养的皮肤来源的黑色素细胞，以及在视网膜色素上皮细胞和葡萄膜黑色素细胞。在四种不同的遗传背景中，Pmel的失活对毛色表型只有轻微的影响，在也携带棕色/Tyrp 1突变的小鼠中效果最明显。这种表型与小鼠自发银突变相似，强烈表明先前描述的脊椎动物中对色素沉着有更显著影响的其他等位基因是显性负突变。尽管对可见色素沉着有轻微影响，但Pmel的失活导致毛发中真黑素含量的大幅降低，这表明PMEL对维持有效的表皮色素沉着具有关键作用。长期以来，色素沉着一直是研究基因如何作用和相互作用的主要模型。PMEL基因编码一种蛋白质，这种蛋白质只存在于色素产生细胞的黑素体中。PMEL基因的突变是动物中一些引人注目的颜色表型的基础，包括鸡中的显性白色、马中的银色和狗中的山鸟色，但尚未在哺乳动物中发现导致该基因完全失活的自发突变。我们现在已经开发了PMEL敲除小鼠，以进一步研究该蛋白的功能。我们发现，缺乏PMEL的小鼠具有几乎正常的可见色素沉着。然而，PMEL的丧失对皮肤、毛发和眼睛中的黑素体的形态具有显著影响，使得野生型动物中的正常杆状黑素体在敲除小鼠中是球形的。基因敲除的动物毛发中黑色素的含量也大幅减少。该研究证实，PMEL对维持正常的色素产生具有关键作用。
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. Pigmentation has since long constituted a prime model to study how genes act and interact. The PMEL gene encodes a protein exclusively found in the melanosomes of pigment-producing cells. 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 now developed a PMEL knockout mouse to further study the function of this protein. We show that mice lacking PMEL have almost normal visible pigmentation. However, loss of PMEL has a dramatic effect on the morphology of the melanosomes in skin, hair, and eye, such that the normally rod-shaped melanosomes in wild-type animals are spherical in the knockout mice. The knockout animals also have a substantial reduction in the content of black pigment in hair. The study establishes that PMEL has a critical role for maintaining normal pigment production.
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