PROJECT SUMMARY Different regions of skin exhibit distinct properties and functions, including their patterns of hair follicle distribution and regenerative properties. Hair loss diseases often have regional effects due to this variation in skin biology. An extremely common example in both men and women is androgenetic alopecia, or AGA, also known as male pattern baldness and female pattern hair loss. AGA affects only scalp hair, and is characterized by disruption of signaling in and around the hair follicle (HF) that leads to inhibition of the hair growth cycle and hair follicle miniaturization. Hair loss diseases can have negative psychological, social, and financial impacts. Current treatments are only partially effective, and the molecular basis for regional variation in skin and hair growth is not well-characterized. Delineating the mechanisms underlying skin and hair heterogeneity has the potential to identify improved therapeutic approaches to hair loss and skin diseases. Wnt/β-catenin signaling is crucial for the initiation, development, and regeneration of hair, and can be modulated by endogenous secreted Wnt inhibitors. Dkk2 and Sostdc1 are secreted Wnt inhibitors that have regionally distinct expression patterns, with relatively higher expression levels in regions of embryonic mouse skin that develop poorly regenerative hair follicles or remain completely hairless. Preliminary data show that Dkk2 and Sostdc1 are also upregulated in the dermal papilla of postnatal HFs as the anagen growth phase ends. The proposed research will test the global hypothesis that Dkk2 and Sostdc1 dictate whether skin will be hair-bearing, determine HF size and regenerative capacity, and control adult HF cycling. Aim 1 will delineate the roles of Dkk2 and Sostdc1 in HF patterning during embryogenesis using Dkk2/Sostdc1 global null mice. Aim 2 will determine the postnatal functions of these inhibitors in regulating HF size and cycling independent of their embryonic roles by inducing deletion postnatally in Dkk2/Sostdc1 floxed mice. Successful completion of the proposed aims has the potential to identify novel therapeutic targets for hair loss diseases and will provide the candidate with rigorous training in experimental techniques and science communication that is essential for an independent research career. Supplemented with the proposed mentorship experiences and collaborative intellectual environment, this fellowship will accelerate the career progress of a promising PhD Candidate who is strongly committed to skin development and regeneration research.