Yang Qian, Kurotani Reiko, Yamada Atsushi, Kimura Shioko, Gonzalez Frank J
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Endocrinology. 2006 Oct;147(10):4772-80. doi: 10.1210/en.2006-0437. Epub 2006 Jul 20.
To identify the potential functions of peroxisome proliferator-activated receptor alpha (PPARalpha) in skin development, transgenic mice were generated to target constitutively activated PPARalpha (VP16PPARalpha) to the stratified epithelia by use of the keratin K5 promoter. In addition to marked alterations in epidermal development, the transgenic mice had a severe defect in lactation during pregnancy resulting in 100% pup mortality. In this study, the alteration of mammary gland development in these transgenic mice was investigated. The results showed that expression of the VP16PPARalpha transgene during pregnancy resulted in impaired development of lobuloalveoli, which is associated with reduced proliferation and increased apoptosis of mammary epithelia. Mammary epithelia from transgenic mice also showed a significant reduction in the expression of beta-catenin and a down-regulation of one of its target genes, cyclin D1, which is thought to be required for lobuloalveolar development. Furthermore, upon PPARalpha ligand treatment, similar effects on lobuloalveolar development were observed in wild-type mice, but not in PPARalpha-null mice. These findings suggest that PPARalpha activation has a marked influence in mammary lobuloalveolar development.
为了确定过氧化物酶体增殖物激活受体α（PPARα）在皮肤发育中的潜在功能，通过使用角蛋白K5启动子，构建了转基因小鼠，使组成型激活的PPARα（VP16PPARα）靶向分层上皮。除了表皮发育的明显改变外，转基因小鼠在怀孕期间的泌乳存在严重缺陷，导致100%的幼崽死亡。在本研究中，对这些转基因小鼠乳腺发育的改变进行了研究。结果表明，怀孕期间VP16PPARα转基因的表达导致小叶腺泡发育受损，这与乳腺上皮细胞增殖减少和凋亡增加有关。转基因小鼠的乳腺上皮细胞中β-连环蛋白的表达也显著降低，其靶基因之一细胞周期蛋白D1的表达下调，而细胞周期蛋白D1被认为是小叶腺泡发育所必需的。此外，用PPARα配体处理后，在野生型小鼠中观察到对小叶腺泡发育有类似影响，但在PPARα基因敲除小鼠中未观察到。这些发现表明，PPARα激活对乳腺小叶腺泡发育有显著影响。
