Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis
Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis
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DOI：
10.1038/35036595
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发表时间：
2000-10-05
期刊：
影响因子：
64.8
通讯作者：
Chambon, P
中科院分区：
文献类型：
--
作者：
Li, M;Indra, AK;Chambon, P
类维生素A (RAR) 和维生素 D (VDR) 以及一些其他配体（TR、PPAR 和 LXR）的核受体可能对哺乳动物表皮的发育和稳态至关重要(1-8)。据信这些受体与类视黄醇 X 受体 (RXR) 形成异二聚体，充当转录调节因子 (9,10)。然而，大多数旨在确定其在皮肤中的生理功能的遗传方法尚无定论，这要么是由于基因敲除中受体同种型之间的多效性和冗余，要么是由于对转基因小鼠显性失活突变体研究的模棱两可的解释(1,13-15)。此外，RXR α（主要皮肤 RXR 同种型）的敲除在皮肤形成之前在子宫内是致命的 (11,12,16,17)。在这里，我们通过开发一种有效的技术来在小鼠中产生时空控制的体细胞突变，解决了这些问题。我们使用他莫昔芬诱导型 Cre-ER(T) 重组酶 (18,19) 选择性地消除成年小鼠角质形成细胞中的 RXR α。我们发现 RXR α 可能通过 RXR/VDR 异二聚体在毛发循环以及表皮角质形成细胞增殖和分化中发挥关键作用。
Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some other ligands (TRs, PPARs and LXRs), may be critical in the development and homeostasis of mammalian epidermis(1-8). It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcriptional regulators(9,10). However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing either to pleiotropic effects and redundancies between receptor isotypes in gene knockouts, or to equivocal interpretation of dominant-negative mutant studies in transgenic mice(1,13-15). Moreover, knockout of RXR alpha, the main skin RXR isotype, is lethal in utero before skin formation(11,12,16,17). Here we have resolved these problems by developing an efficient technique to create spatiotemporally controlled somatic mutations in the mouse. We used tamoxifen-inducible Cre-ER(T) recombinases(18,19) to ablate RXR alpha selectively in adult mouse keratinocytes. We show that RXR alpha has key roles in hair cycling, probably through RXR/VDR heterodimers, and in epidermal keratinocyte proliferation and differentiation.