Slominski Andrzej, Plonka Przemyslaw M, Pisarchik Alexander, Smart James L, Tolle Virginie, Wortsman Jacobo, Low Malcolm J
Department of Pathology and Laboratory Medicine, University of Tennessee, Memphis, Tennessee 38163, USA.
Endocrinology. 2005 Mar;146(3):1245-53. doi: 10.1210/en.2004-0733. Epub 2004 Nov 24.
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 alpha 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 alpha 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.
促肾上腺皮质激素原（POMC）缺陷小鼠（Pomc-/-）的原始品系是通过同源重组在源自129X1/SvJ（A(w)/A(w)）的胚胎干细胞中产生的，使用的靶向构建体删除了Pomc基因的外显子3，该外显子编码所有已知的功能性POMC衍生肽，包括α-MSH。尽管这些Pomc-/-小鼠表现出肾上腺发育不全和肥胖，类似于儿童POMC缺乏综合征，但它们的刺豚鼠毛色仅发生了细微改变。为了进一步研究在缺乏POMC肽的情况下毛发色素沉着的机制，我们在非刺豚鼠（a/a）129;B6杂交遗传背景下研究了野生型（Pomc+/+）、杂合子（Pomc+/-）和纯合子（Pomc-/-）小鼠。所有三种基因型都有相似的黑色皮毛色素沉着，耳朵后面、乳头周围和肛周区域有黄色毛发，这是近交C57BL/6小鼠的特征。组织学和电子顺磁共振光谱检查表明，Pomc-/-小鼠背部皮肤的毛囊结构和真黑素色素沉着正常发育；然而，相应的分子分析排除了α-MSH和促肾上腺皮质激素（ACTH）的局部产生，因为在皮肤中未检测到Pomc或假定的Pomc假基因mRNA。因此，129;B6 Pomc基因敲除突变小鼠尽管先天性缺乏黑皮质素配体，但仍产生大量真黑素毛发色素沉着。这些结果表明，要么小鼠黑皮质素受体1具有足够的基础活性来触发和维持体内真黑素生成，要么冗余的非黑皮质素途径补偿了黑皮质素缺乏。后者意味着对黑素生成的反馈控制，也有可能这两种机制在毛囊中共同起作用。
