Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Stem Cells. 2013 Sep;31(9):1921-31. doi: 10.1002/stem.1438.
The key signaling networks regulating mammary stem cells are poorly defined. The leucine-rich repeat containing G protein-coupled receptor (Lgr) family has been implicated in intestinal, gastric, and epidermal stem cell functions. We investigated whether Lgr4 functions in mammary gland development and mammary stem cells. We found that Lgr4(-/-) mice had delayed ductal development, fewer terminal end buds, and decreased side-branching. Crucially, the mammary stem cell repopulation capacity was severely impaired. Mammospheres from Lgr4(-/-) mice showed decreased Wnt signaling. Wnt3a treatment prevented the adverse effects of Lgr4 loss on organoid formation. Chromatin immunoprecipitation analysis indicated that Sox2 expression was controlled by the Lgr4/Wnt/β-catenin/Lef1 pathway. Importantly, Sox2 overexpression restored the in vivo mammary regeneration potential of Lgr4(-/-) mammary stem cells. Therefore, Lgr4 activates Sox2 to regulate mammary development and stem cell functions via Wnt/β-catenin/Lef1.
调控乳腺干细胞的关键信号网络尚未完全明确。富含亮氨酸重复序列的 G 蛋白偶联受体（Lgr）家族与肠道、胃和表皮干细胞功能有关。本研究旨在探究 Lgr4 是否参与乳腺发育和乳腺干细胞功能。结果发现，Lgr4 敲除小鼠的乳腺导管发育延迟，终末芽数量减少，侧芽分支减少。更重要的是，乳腺干细胞的再群体能力严重受损。Lgr4 敲除小鼠的乳腺球体中 Wnt 信号降低。Wnt3a 处理可预防 Lgr4 缺失对类器官形成的不利影响。染色质免疫沉淀分析表明 Sox2 的表达受 Lgr4/Wnt/β-catenin/Lef1 通路的调控。重要的是，Sox2 过表达可恢复 Lgr4 敲除小鼠乳腺干细胞的体内乳腺再生潜能。因此，Lgr4 通过 Wnt/β-catenin/Lef1 激活 Sox2 来调节乳腺发育和干细胞功能。
