A sex hormone-BDNF-TrkB axis directs sympathetic innervation in the mouse mammary gland

Stromal-epithelial interactions underlie fundamental tissue morphogenesis in normal development, tissue regeneration and cancer. Peripheral nerves are increasingly implicated as important stromal drivers of normal and malignant epithelial tissue biology. In the mammary gland, epithelial cell fate is highly dependent on stromal cues during distinct stages of postnatal growth which are triggered by ovarian sex hormones estrogen and progesterone. However, the effects of sex hormones on peripheral nerves in the postnatal mammary gland is largely unknown. Here, we uncover extensive changes in peripheral sympathetic innervation in the mammary stromal microenvironment during puberty and pregnancy which are periods of active postnatal mammary epithelial growth. We find that sex hormones induce sympathetic axonal branching through an intricate hormone-epithelial-nerve cross-talk. Specifically, estrogen and progesterone stimulate the expression of brain-derived neurotrophic factor (BDNF) in mammary hormone receptor- expressing luminal epithelial cells which acts on Tropomyosin receptor kinase B (TrkB)- expressing sympathetic nerves to activate BDNF-TrkB signaling. Our findings illustrate a previously unrecognized capacity of hormone-sensing epithelial cells to modulate sympathetic innervation, providing a framework for understanding nerve dynamics during tissue regeneration and cancer.