The formation of renal cysts is a leading cause of end-stage renal failure, and given the limited management options for this disorder, understanding its cellular basis is of paramount importance. Data from syndromic and non-syndromic forms of cyst formation, such as the polycystic kidney diseases (PKD), nephronophthisis (NPH) and Bardet-Biedl syndrome (BBS), have yielded important insights and hold the potential for new therapeutic approaches. In vitro and in vivo studies have indicated a major role for renal sensory cilia and the hypothesis that these structures sense extracellular fluid signaling has gained significant momentum. However, the nature and effect of the extracellular signal(s) remains. Recent evidence suggests that the cilium and basal body are responsible for transducing morphogenetic signals. In agreement with this notion, our preliminary data suggest that disruption of the basal body affects the propagation of Wnt signaling and that such mutations interact genetically with members of the non-canonical (beta-catenin independent) Wnt signaling pathway. Here we propose to investigate the link between renal cystic disease and Wnt signaling. First, we will establish the renal phenotype of mice ablated specifically for Bbs1, Bbs4 and Bbs6, all of which have been implicated in ciliary/basal body function, and monitor the activity of beta-catenin during renal development by means of a lacZ reporter. In parallel, to explore the potential role of the basal body in common renal disease, we will explore the possible synergy between BBS and PKD by introducing a heterozygous Pkd1 or Pkhdl null allele in Bbs mutant lines and determine whether there is genetic interaction. Second, we will investigate the biochemical nature of the Wnt defect in basal body mutants and suppressants and determine the behavior and cellular distribution of a series of Wnt-responsive proteins such as b-catenin and Dishevelled. Finally, we will combine the power of robust in vitro Wnt response assays with recent studies that heavily enriched for novel ciliary and basal body proteins to identify new components of the cilium that regulate the intracellular Wnt response. Establishing the link between the basal body and the cilium with Wnt signaling represents a potential paradigm shift in renal cystic disease and will likely lead to a profoundly novel means of approaching treatment and prevention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Rasooly, Rebekah S
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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