Project Summary / Abstract Normal skin function is thought to depend on sebaceous glands (SGs), which are paired appendages typically associated with hair follicles. The main purpose of SGs is to secrete sebum, a lipid-rich substance that acts on the skin to regulate barrier function and hydration, while possibly possessing anti-oxidant and anti-microbial properties. Aberrant SGs have been associated with skin pathologies such as acne and scarring alopecia, but their functional roles in disease remain unclear. Although numerous genes and signaling pathways have been implicated in maintaining SGs, few studies have characterized the mechanisms by which these factors modulate SG stem cell differentiation, and whether their effects are direct or indirect. Our previous studies have found that Notch signaling simultaneously exerts dual opposing effects on SGs: Whereas Notch directly promotes SG stem cell differentiation, this pathway also indirectly suppresses SGs by regulating proper differentiation in the surface interfollicular epidermis. We further observed that a PPARγ/K5 double-positive population likely serves as the immediate progenitors that give rise to differentiated sebocytes in the gland. This proposal seeks to identify some of the complex factors that regulate SG stem cells and to test the requirement for SGs in maintaining normal skin function. In Aim 1, we will examine how Notch directly promotes SG stem cell differentiation, and evaluate novel genes that may modulate SG function. In Aim 2, we will determine how disruption of Notch-dependent epidermal differentiation causes SGs to enlarge. In Aim 3, we will assess the consequences of deleting SGs throughout the skin. Altogether, these studies will characterize how SG stem cells are regulated, both locally and from a distance, and potentially uncover novel functions for these glands. These studies build upon the emerging concept that different cellular sub- compartments in the skin are intricately linked and communicate with each other through a variety of signaling cues.