Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation.
Ablation of beta1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation.
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DOI：
10.1083/jcb.200503144
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发表时间：
2005-11-21
影响因子：
7.8
通讯作者：
Streuli, Charles H
中科院分区：
文献类型：
--
作者：
Naylor, Matthew J;Li, Na;Cheung, Julia;Lowe, Emma T;Lambert, Elise;Marlow, Rebecca;Wang, Pengbo;Schatzmann, Franziska;Wintermantel, Timothy;Schuetz, Gunther;Clarke, Alan R;Mueller, Ulrich;Hynes, Nancy E;Streuli, Charles H
整合素介导的粘附调节一系列组织的发育和功能;然而，对其在腺上皮中的作用知之甚少。为了评估β1整合素的贡献，我们在小鼠乳腺发育的不同阶段的管腔上皮和培养的原代乳腺上皮中条件性地缺失了其基因。体内β1整合素的缺失导致肺泡形成和泌乳受损。培养的β1整合素缺失细胞显示异常的粘着斑功能和信号转导，不能形成或维持极化腺泡。在体内，上皮细胞与细胞外基质分离，但仍相互结合，没有发生明显的凋亡。β1整合素缺失的乳腺上皮细胞由于缺陷的Stat 5激活而不响应于催乳素刺激而分化。在分化开始后β1整合素缺失的小鼠中，肺泡形态缺陷较少，但在乳蛋白和乳脂产生以及Stat 5活化中也观察到主要缺陷，表明β1整合素在催乳素信号传导中的容许作用。这项研究表明，β1整合素是至关重要的腺上皮细胞的肺泡形态发生和维持其分化的功能。此外，它提供了整合素和细胞因子信号通路之间的合作的遗传证据。
Integrin-mediated adhesion regulates the development and function of a range of tissues; however, little is known about its role in glandular epithelium. To assess the contribution of β1 integrin, we conditionally deleted its gene in luminal epithelia during different stages of mouse mammary gland development and in cultured primary mammary epithelia. Loss of β1 integrin in vivo resulted in impaired alveologenesis and lactation. Cultured β1 integrin–null cells displayed abnormal focal adhesion function and signal transduction and could not form or maintain polarized acini. In vivo, epithelial cells became detached from the extracellular matrix but remained associated with each other and did not undergo overt apoptosis. β1 integrin–null mammary epithelial cells did not differentiate in response to prolactin stimulation because of defective Stat5 activation. In mice where β1 integrin was deleted after the initiation of differentiation, fewer defects in alveolar morphology occurred, yet major deficiencies were also observed in milk protein and milk fat production and Stat5 activation, indicating a permissive role for β1 integrins in prolactin signaling. This study demonstrates that β1 integrin is critical for the alveolar morphogenesis of a glandular epithelium and for maintenance of its differentiated function. Moreover, it provides genetic evidence for the cooperation between integrin and cytokine signaling pathways.