Autosomal Dominant Polycystic Kidney Disease (ADPKD) strikes 1 in 1000 individuals, often resulting in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95 percent of all cases. ADPKD1 and ADPKD2 are phenotypically indistinguishable, leading to the hypothesis that pathology is caused by defects in the same pathway. The cellular roles of the PKD 1 and PKD2 gene products (polycystin 1 and polycystin 2, respectively) still remain unknown. The powerful molecular genetic tools of the nematode Caenorhabditis elegans (C. Elegans)will enable us to address fundamental questions regarding polycystin function and physiological relevance of partner interactions. The C. elegans homologs of PKD1 and PKD2, LOV-1 and PKD-2, are coexpressed and colocalized in three types of male chemosensory neurons: the cephalic CEMs, the HOB hook neuron, and the ray neurons. Furthermore, lov-1 and pkd-2 are required in the male nervous system for the mating behaviors of response to hermaphrodite contact and location of the hermaphrodite vulva (Lov). The C. elegans homolog of Tg737 (a murine gene associated with Autosomal Recessive PKD) exhibits an expression pattern that partially overlaps with lov-1 and pkd-2 and maps closely to osm-5. osm-5 is also necessary for response and Lov behavior, suggesting that the three may operate in the same cell. This proposal is designed to test the hypothesis that LOV-1, PKD-2, and possibly CeTg737 act in a common pathway. Experiments will explore several models of LOV-1, PKD-2, and CeTg737 function. Hypotheses include the following: CeTg737 may localize LOV-1 and PKD-2 to the cilia where LOV-1 and PKD-2 are required for function. Moreover, LOV-1 may be involved in transducing an extracellular signal via PKD-2 in the cilia, culminating in activation of an intracellular signaling pathway. Alternatively, LOV-1 and PKD-2 may be involved in the formation and maintenance of sensory cilia or the establishment and maintenance of neuronal cell polarity. A number of complementary studies are proposed to address the function of the C. elegans polycystins and CeTg737 in male mating behavior. Genetic and molecular interactions between lov-1, pkd-2, and CeTg737 will be explored. Cellular functions of the C. elegans polycystins will be ascertained. The function of CeTg737 in male sensory mating behaviors will be determined. New components in the LOV/PKD pathway will be isolated. These experiments will analyze LOV/PKD at the cellular, genetic, and molecular levels.
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