Our long-term goal is to understand the role of the basonuclin gene in skin and hair follicle biology. Basonuclin (BNC1) is a zinc finger protein found in abundance in the keratinocytes of the epidermis and hair follicle. We believe that it coordinates activity of other genes through transcription factor activity. Our biochemical and bioinformatic studies show that BNC1 regulates transcription of genes in six different pathways. The BNC1 regulatory network is linked to pathways such as EGFR, p38 MAPK and TGFalpha. These genes control important cellular functions like proliferation, migration and differentiation. BNC1 is up-regulated in basal cell carcinoma (BCC). Our study of a Bnc1 knock out model suggests that it is required for hair follicle regeneration after hairplucking, and Bnc1-null mutation delays restoration of hair follicular stem cells after hairplucking. In this proposal, we will evaluate the role of Bnc-1 and Bnc-2 in skin regeneration, wound repair and hair follicle cycling. We will characterize how the Bnc1- null mutation affects hair regeneration, including determination of which cellular processes are affected by this mutation and what molecular perturbations are caused by Bnc1-null mutation. By examining Bnc-1 and Bnc-2 single and double knockout mice, we will assess the contribution of these genes to maintenance of epithelial stem cells in the bulge as well as the response of these cells to injury. Using mice that we have developed to study the fate of bulge stem cells, we will trace the movement and contribution of bulge cells in the Bnc mutant mice following hair plucking and skin injury. We will study the interaction of BNC with the EGFr pathway using mice with deleted receptors or mice expressing inhibitors of the EGFr pathway. Changes in proliferation, differentiation and migration will be assessed in both in vitro and in vivo assays. Overall, our research will discern the effect of deleting Bnc-1 and Bnc-2 in the cutaneous epithelium. The role of Bnc's in the EGFr pathway will be discerned. The studies will impact on understanding stem cell biology and the role of Bnc's in wound healing, hair cycling and skin regeneration.