California Pacific Medical Center Research Institute, San Francisco, CA 94107, USA.
J Cell Sci. 2010 Nov 1;123(Pt 21):3683-92. doi: 10.1242/jcs.070680. Epub 2010 Oct 12.
Receptors for basement membrane (BM) proteins, including dystroglycan (DG), coordinate tissue development and function by mechanisms that are only partially defined. To further elucidate these mechanisms, we generated a conditional knockout of DG in the epithelial compartment of the mouse mammary gland. Deletion of DG caused an inhibition of mammary epithelial outgrowth and a failure of lactation. Surprisingly, loss of DG in vivo did not disrupt normal tissue architecture or BM formation, even though cultured Dag1-null epithelial cells failed to assemble laminin-111 at the cell surface. The absence of DG was, however, associated with a marked loss in activity of signal transducer and activator of transcription 5 (STAT5). Loss of DG perturbed STAT5 signaling induced by either prolactin or growth hormone. We found that DG regulates signaling by both hormones in a manner that is dependent on laminin-111 binding, but independent of the DG cytoplasmic domain, suggesting that it acts via a co-receptor mechanism reliant on DG-mediated laminin assembly. These results demonstrate a requirement for DG in the growth and function of a mammalian epithelial tissue in vivo. Moreover, we reveal a selective role for DG in the control of multiple STAT5-dependent hormone signaling pathways, with implications for numerous diseases in which DG function is compromised.
基底膜 (BM) 蛋白受体，包括 dystroglycan (DG)，通过部分定义的机制协调组织发育和功能。为了进一步阐明这些机制，我们在小鼠乳腺的上皮细胞中生成了 DG 的条件性敲除。DG 的缺失导致乳腺上皮细胞的生长受到抑制和泌乳失败。令人惊讶的是，DG 的缺失在体内并没有破坏正常的组织结构或 BM 形成，尽管培养的 Dag1 缺失的上皮细胞不能在细胞表面组装层粘连蛋白-111。然而，DG 的缺失与信号转导和转录激活因子 5 (STAT5) 的活性显著丧失有关。DG 的缺失扰乱了由催乳素或生长激素诱导的 STAT5 信号。我们发现，DG 通过依赖于层粘连蛋白-111 结合的方式调节两种激素的信号，但不依赖于 DG 胞质结构域，这表明它通过依赖于 DG 介导的层粘连蛋白组装的共受体机制发挥作用。这些结果表明 DG 在体内哺乳动物上皮组织的生长和功能中是必需的。此外，我们揭示了 DG 在控制多种 STAT5 依赖性激素信号通路中的选择性作用，这对 DG 功能受损的许多疾病具有重要意义。
