Orthologs of the mammalian genes encoding the aryl hydrocarbon receptor (AHR-1) and its dimerization partner, aryl hydrocarbon nuclear translocator (AHA-1) were detected in the nematode, Caenorhabditis elegans. The function of these genes in normal development is unknown but the presence of the orthologs in C. elegans will allow a genetic approach to understanding the normal function of these genes. The specific aims of this research are: 1) To determine the cellular and subcellular location of AHR-1 and AHA-1, the proteins encoded by the orthologus genes 2) Isolation and analysis of mutants defective in ahr-1 or aha-1 function 3) Test the hypothesis that endogenous ligands regulate nuclear translocation of AHR-1 during normal development. In a complementary approach, nuclear translocation of FG'P-tagged AHR-1 will be monitored in vivo. 4) Test the hypothesis that nuclear localization of AHR-1 is dependent upon its dimerization partner AHA-1. The subcellular location of AHR-1 will be examined in existing mutants that lack aha-1 function.
Although the normal function for these genes is unknown in either the mammalian or nematode systems, it is known that the mammalian receptor encoded by AHR-1 is a ligand-inducible transcription factor that can be inappropriately activated by environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin leading to carcinogenic, teratogenic, hepatotoxic and immunotoxic effects. The information resulting from these experiments will provide insight into the function of these genes in normal development as well as the causes for the inappropriate activation by environmental pollutants. Such information will become increasingly critical as the pollutant load in the atmosphere increases.
