Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
PLoS One. 2014 Apr 9;9(4):e92735. doi: 10.1371/journal.pone.0092735. eCollection 2014.
Fibroblast growth factor (FGF) signaling is essential for vertebrate organogenesis, including mammary gland development. The mechanism whereby FGF signaling is regulated in the mammary gland, however, has remained unknown. Using a combination of mouse genetics and 3D ex vivo models, we tested the hypothesis that Spry2 gene, which encodes an inhibitor of signaling via receptor tyrosine kinases (RTKs) in certain contexts, regulates FGF signaling during mammary branching. We found that Spry2 is expressed at various stages of the developing mammary gland. Targeted removal of Spry2 function from mammary epithelium leads to accelerated epithelial invasion. Spry2 is up-regulated by FGF signaling activities and its loss sensitizes mammary epithelium to FGF stimulation, as indicated by increased expression of FGF target genes and epithelia invasion. By contrast, Spry2 gain-of-function in the mammary epithelium results in reduced FGF signaling, epithelial invasion, and stunted branching. Furthermore, reduction of Spry2 expression is correlated with tumor progression in the MMTV-PyMT mouse model. Together, the data show that FGF signaling modulation by Spry2 is essential for epithelial morphogenesis in the mammary gland and it functions to protect the epithelium against tumorigenesis.
成纤维细胞生长因子 (FGF) 信号对于脊椎动物器官发生，包括乳腺发育，是必不可少的。然而，FGF 信号在乳腺中的调节机制仍然未知。我们使用小鼠遗传学和 3D 体外模型的组合，检验了以下假设：Spry2 基因在某些情况下编码信号转导受体酪氨酸激酶 (RTKs) 的抑制剂，调节乳腺分支过程中的 FGF 信号。我们发现 Spry2 在乳腺发育的各个阶段都有表达。从乳腺上皮细胞中靶向去除 Spry2 功能会导致上皮细胞侵袭加速。FGF 信号活性上调 Spry2 的表达，其缺失使乳腺上皮细胞对 FGF 刺激敏感，表现为 FGF 靶基因的表达增加和上皮细胞侵袭。相比之下，乳腺上皮细胞中 Spry2 的功能获得会导致 FGF 信号减少、上皮细胞侵袭和分支停滞。此外，Spry2 表达的减少与 MMTV-PyMT 小鼠模型中的肿瘤进展相关。总之，这些数据表明 Spry2 对 FGF 信号的调节对于乳腺上皮形态发生是必不可少的，它的功能是保护上皮细胞免受肿瘤形成。
