Prolactin, growth hormone, and epidermal growth factor activate stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects
Prolactin, growth hormone, and epidermal growth factor activate stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects
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DOI：
10.1006/dbio.2000.9961
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发表时间：
2001-01-01
影响因子：
2.7
通讯作者：
Hennighausen, L
中科院分区：
文献类型：
--
作者：
Gallego, MI;Binart, N;Hennighausen, L
催乳素（Prl）诱导的Stat（信号转导和转录激活因子）5的磷酸化被认为是功能性乳腺发育和分化的关键事件。我们现在证明，除了Prl，生长激素（GH）和表皮生长因子（EGF）也可以激活乳腺组织中的Stat5。我们研究了这些激素在乳腺发育中的作用，使用灭活了各自受体的小鼠。虽然Prl受体（PrlR）缺失的小鼠是不育的，但我们能够通过黄体酮治疗维持少数小鼠的妊娠。通过Stat5的磷酸化状态和乳蛋白基因的表达来评估，这些小鼠的乳腺组织严重发育不全，分化有限。PrlR +/-小鼠在妊娠期间表现出乳腺发育和肺泡分化受损，这与Stat5a和5b磷酸化水平降低以及乳蛋白基因表达受损有关。这些小鼠的腺体发育在怀孕第13天左右停止。Prl仅在上皮中激活Stat5，而GH和EGF优先在基质中激活Stat5。为了评估GH受体（GHR）在乳腺中的相关性，我们将GHR缺失的上皮移植到野生型小鼠清除的脂肪垫中。这些实验表明，上皮细胞中的GHR并不是功能性乳腺发育所必需的。同样，上皮中的EGFR也不是肺泡发育所必需的。相比之下，上皮PrlR是乳腺发育和妊娠期间乳蛋白基因表达所必需的。虽然生长激素不是肺泡发育所必需的，但我们能够在prlr缺失小鼠培养的乳腺上皮中证明其产乳功能。然而，ghr缺失小鼠的导管发育受损，这支持了GH信号通过间质室传递的观点。我们的研究结果表明，GH、Prl和EGF在不同的区室中激活Stat5，这反过来反映了它们在导管和肺泡发育和分化中的特定作用。
Prolactin (Prl)-induced phosphorylation of Stat (signal transducer and activator of transcription) 5 is considered a key event in functional mammary development and differentiation. We now demonstrate that not only Prl, but also growth hormone (GH) and epidermal growth factor (EGF), can activate Stat5 in mammary tissue. We investigated the roles of these hormones in mammary development using mice in which the respective receptors had been inactivated. Although Prl receptor (PrlR)-null mice are infertile, we were able to maintain pregnancies in a few mice by treatment with progesterone. Mammary tissue in these mice was severely underdeveloped and exhibited limited differentiation as assessed by the phosphorylation status of Stat5 and the expression of milk protein genes. PrlR +/- mice showed impaired mammary development and alveolar differentiation during pregnancy, which corresponded with reduced phosphorylation levels of Stat5a and 5b, and impaired expression of milk protein genes. Development of the glands in these mice was arrested at around day 13 of pregnancy. While Prl activated Stat5 only in the epithelium, GH and EGF activated Stat5 preferentially in the stroma. To assess the relevance of the GH receptor (GHR) in the mammary gland, we transplanted GHR-null epithelium into cleared fat pads of wild-type mice. These experiments demonstrated that the GHR in the epithelium is not required for functional mammary development. Similarly, the EGFR in the epithelium is not required for alveolar development. In contrast, epithelial PrlR is required for mammary development and milk protein gene expression during pregnancy. Although GH is not required for alveolar development, we were able to demonstrate its lactogenic function in cultured mammary epithelium from PrlR-null mice. However, ductal development in GHR-null mice was impaired, supporting the notion that GH signals through the stromal compartment. Our findings demonstrate that GH, Prl, and EGF activate Stat5 in separate compartments, which in turn reflects their specific roles in ductal and alveolar development and differentiation.