Sympathetic Nerve Signal is Critical for Regulating Mammary Gland Development and Mammary Stem Cell Activity

Adult stem cell activity and organ development are elaborately regulated by microenvironmental signals. However, little is known about the regulatory effects of microenvironmental sympathetic nerve signals on organ development and stem cell activity. Here, using a mouse mammary gland model, we determined the regulatory function of sympathetic nerve system (SNS) on mammary development and mammary stem cell activity. Our results indicated that depletion of sympathetic nerve signals delayed the elongation of mammary ducts during puberty and pregnancy, and lead to the loss of mammary stem cells (MaSCs). In vitro three-dimensional (3D) culture and in vivo transplantation analyses indicated that the loss of sympathetic nerve signals inhibits the self-renewal and reconstruction activity of mammary stem cells, while the activation of sympathetic nerve signals promotes the self-renewal and reconstruction activity of mammary stem cells. Mechanistically, we found that sympathetic nerve signals regulate the activity of mammary stem cells and mammary development through the PI3K/ERK pathway. Together, our study reveals the function of sympathetic nervous signals in maintaining mammary homeostasis and regulating mammary stem cell activity, providing a novel view for the nervous system's regulation of organ development.