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首页> 外文期刊>Molecular and Cellular Biology >Impaired Alveologenesis and Maintenance of Secretory Mammary Epithelial Cells in Jak2 Conditional Knockout Mice
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Impaired Alveologenesis and Maintenance of Secretory Mammary Epithelial Cells in Jak2 Conditional Knockout Mice

机译：Jak2条件性基因敲除小鼠的肺泡形成和分泌性乳腺上皮细胞的受损。

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Jak2 is a hormone-receptor-coupled kinase that mediates the tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat). The biological relevance of Jak2-Stat signaling in hormone-responsive adult tissues is difficult to investigate since Jak2 deficiency leads to embryonic lethality. We generated Jak2 conditional knockout mice to study essential functions of Jak2 during mammary gland development. The mouse mammary tumor virus-Cre-mediated excision of the first coding exon resulted in a Jak2 null mutation that uncouples signaling from the prolactin receptor (PRL-R) to its downstream mediator Stat5 in the presence of normal and supraphysiological levels of PRL. Jak2-deficient females were unable to lactate as a result of impaired alveologenesis. Unlike Stat5a knockouts, multiple gestation cycles could not reverse the Jak2-deficient phenotype, suggesting that neither other components of the PRL-R signaling cascade nor other growth factors and their signal transducers were able to compensate for the loss of Jak2 function to activate Stat5 in vivo. A comparative analysis of Jak2-deficient mammary glands with transplants from Stat5a/b knockouts revealed that Jak2 deficiency also impairs the pregnancy-induced branching morphogenesis. Jak2 conditional mutants therefore resemble PRL-R knockouts more closely, which suggested that Jak2 deficiency might affect additional PRL-R downstream mediators other than Stat5a and Stat5b. To address whether Jak2 is required for the maintenance of PRL-responsive, differentiating alveolar cells, we utilized a transgenic strain that expresses Cre recombinase under regulatory elements of the whey acidic protein gene (Wap). The Wap-Cre-mediated excision of Jak2 resulted in a negative selection of differentiated alveolar cells, suggesting that Jak2 is required not only for the proliferation and differentiation of alveolar cells but also for their maintenance during lactation.
机译：Jak2是一种激素受体偶联激酶，可介导酪氨酸磷酸化以及信号转导子和转录激活子的激活（Stat）。由于Jak2缺乏导致胚胎致死性，因此难以研究激素反应性成人组织中Jak2-Stat信号传导的生物学相关性。我们生成了Jak2条件敲除小鼠，以研究Jak2在乳腺发育过程中的基本功能。小鼠乳腺肿瘤病毒-介导的第一个编码外显子的切除导致Jak2无效突变，该突变在正常情况下可将催乳素受体（PRL-R）与其下游介体Stat5的信号解偶联和PRL的超生理水平。由于肺泡形成受损，Jak2缺乏的女性无法泌乳。与Stat5a基因敲除不同，多个妊娠周期不能逆转Jak2缺陷表型，这表明PRL-R信号级联反应的其他成分或其他生长因子及其信号转导子均无法补偿Jak2功能的丧失，从而激活Stat5。体内。 Stat5a / b基因敲除的移植物对Jak2缺陷型乳腺的比较分析表明，Jak2缺陷也损害了妊娠诱导的分支形态发生。因此，Jak2条件突变体更类似于PRL-R基因敲除，这表明Jak2缺乏可能影响除Stat5a和Stat5b之外的其他PRL-R下游介体。为了解决是否需要Jak2来维持PRL反应性，分化的肺泡细胞，我们利用了一种在乳清酸性蛋白基因（ Wap ）调控元件下表达Cre重组酶的转基因菌株。 Wap-Cre 介导的Jak2切除导致分化的肺泡细胞的阴性选择，这表明Jak2不仅是肺泡细胞的增殖和分化所必需的，而且在泌乳期间也需要它们的维持。

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