AHR FUNCTION IN MURINE STRATIFIED SQUAMOUS EPITHELIA

Exposure to polycyclic and aromatic hydrocarbons results in tissue specific pathological effects including tumor promotion, immunotoxicity, hepatoxicity, and teratogenesis. The Aryl hydrocarbon receptor (AhR) and its partner, the aryl hydrocarbon receptor nuclear translocator (Arnt) dimerize to form a ligand inducible transcription factor responsible for mediating the biological effects of these compounds. These proteins are members of the basic Helix-Loop-Helix-PAS family of transcription factors, and their expression is temporally and spatially regulated during embryogenesis and differentiation. Understanding the biological function of these proteins is key to understanding their role in pathology. However, little is known about the endogenous role of these receptors. The goal of this study is to produce an animal model to study the functioning of the AhR in an intact biological system. Independently, two laboratories have constructed mice lacking AhR, and these animals have differing phenotypes. By producing mice that have the AhR Exon 2 flanked by lox sites, tissue specific knockout mice can be generated through the mating to transgenic mice with the Cre recombinase under tissue specific control. The mouse with the altered AhR gene could also be mated with other Cre transgenic mice to create other conditional knockout animals. Production of mice lacking the AhR only in the replicating compartment of the skin, would circumvent the indirect effects of the gene loss, and allow the study of the role of AhR in differentiating squamous epithelia. This animal, once generated, can be used to study wounding and xenobiotic treatment. The keratinocytes from these mice can be cultured and utilized to study how the AhR gene effects cell type-specific growth and differentiation in vitro, and provide a source for AhR deficient keratinocytes for further studies.