Abstract：
The interactions of environmental compartments with epithelial cells are essential for mammary gland development and homeostasis. Currently, the direct crosstalk between the endothelial niche and mammary epithelial cells remains poorly understood. Here, we show that faciogenital dysplasia 5 (FGD5) is enriched in mammary basal cells (BCs) and mediates critical interactions between basal and endothelial cells (ECs) in the mammary gland. Conditional deletion of Fgd5 reduced, whereas conditional knockin of Fgd5 increased, the engraftment and expansion of BCs, regulating ductal morphogenesis in the mammary gland. Mechanistically, murine mammary BC-expressed FGD5 inhibited the transcriptional activity of activating transcription factor 3 (ATF3), leading to subsequent transcriptional activation and secretion of CXCL14. Furthermore, activation of CXCL14/CXCR4/ERK signaling in primary murine mammary stromal ECs enhanced the expression of HIF-1α-regulated hedgehog ligands, which initiated a positive feedback loop to promote the function of BCs. Collectively, these findings identify functionally important interactions between BCs and the endothelial niche that occur through the FGD5/CXCL14/hedgehog axis.
摘要：
环境区室与上皮细胞的相互作用对于乳腺发育和稳态至关重要。目前,内皮小生境和乳腺上皮细胞之间的直接串扰仍然知之甚少。这里,我们表明，面生殖器发育不良5（FGD5）在乳腺基底细胞（BCs）中富集，并介导乳腺基底细胞和内皮细胞（ECs）之间的关键相互作用。Fgd5的条件缺失减少，而Fgd5的条件敲入增加，BCs的种植和扩展，调节乳腺的导管形态发生。机械上,小鼠乳腺BC表达的FGD5抑制激活转录因子3（ATF3）的转录活性，导致随后的转录激活和CXCL14的分泌。此外，原代小鼠乳腺基质内皮细胞中CXCL14/CXCR4/ERK信号的激活增强了HIF-1α调节的hedgehog配体的表达，它启动了一个正反馈循环，以促进BCs的功能。总的来说，这些发现确定了通过FGD5/CXCL14/hedgehog轴发生的BCs和内皮生态位之间的功能上重要的相互作用。
