Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform
Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform
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DOI：
10.1073/pnas.1732707100
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发表时间：
2003-08-19
影响因子：
11.1
通讯作者：
Conneely, OM
中科院分区：
文献类型：
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作者：
Mulac-Jericevic, B;Lydon, JP;Conneely, OM
黄体酮（P）通过两种核受体PR-A和PR-B调节雌性生殖。虽然这两种受体显示重叠和不同的转录调控特性，其各自的生理作用尚不清楚。为了说明PR-A的生理作用，我们产生了PR-B表达被特异性消除的小鼠模型（PRBKO-/-）。我们表明PRBKO-/-小鼠中PR-A的选择性激活足以引起对P的正常卵巢和子宫反应，但导致乳腺形态发生减少。在没有PR-B的情况下，由于导管和肺泡上皮细胞增殖减少和肺泡上皮存活减少，妊娠相关的导管侧支和小叶肺泡发育显著减少。为了阐明在乳腺中由PR差异调节的分子遗传信号传导途径，我们已经鉴定了bar激活子下的受体（a）bar核下的受体（f）bar配体下的受体κ B（l）bar配体下的受体（RANKL）作为P依赖性肺泡发生的旁分泌介质。此外，我们证明PRBKO-/-小鼠的缺陷与PR-A无法激活RANKL信号通路响应P。我们的数据表明，PR-A和PR-13之间的功能相互作用是不需要生殖活动和选择性调节PR-A活性的促性腺激素激动剂可能对子宫和乳腺增生具有保护作用。
Progesterone (P) regulates female reproduction via two nuclear receptors, PR-A and PR-B. Although both receptors display overlapping and distinct transcription regulatory properties, their individual physiological roles are unclear. To address the physiological role of PR-A, we generated a mouse model in which expression of PR-B was specifically ablated (PRBKO-/-) We show that selective activation of PR-A in PRBKO-/- mice is sufficient to elicit normal ovarian and uterine responses to P but re suits in reduced mammary gland morphogenesis. In the absence of PR-B, pregnancy-associated ductal sidebranching and lobuloalveolar development are markedly reduced due to decreased ductal and alveolar epithelial cell proliferation and decreased survival of alveolar epithelium. in an effort to elucidate the molecular genetic signaling pathways that are differentially regulated by PRs in the mammary gland, we have identified receptor (a) under bar ctivator of (n) under bar uclear (f) under bar actor kappaB (l) under bar igand (RANKL) as a paracrine mediator of P-dependent alveologenesis. Further, we demonstrate that the defects in PRBKO-/- mice are associated with an inability of PR-A to activate the RANKL signaling pathway in response to P. Our data indicate that functional interaction between PR-A and PR-13 is not required for reproductive activity and that selective modulation of PR-A activity by progestin agonists may have a protective effect against both uterine and mammary gland hyperplasias.