Mutations in Polycystin-1 (PKD1) and Polycystin-2 (PKD2) account for all cases of Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common heritable human disease. In addition to their localization and function in primary cilia, polycystins are localized at sites of cell-matrix interactions, indicating they may act there as mechanosensors of the cellular environment. We have modeled polycystic kidney disease in the zebrafish by disrupting the function of polycystin1 and polycystin2. Our results demonstrate that Polycystins function in signaling pathways that sense the compostion of extracellular matrix and generate feedback signals that terminate """"""""fetal"""""""" programs of gene expression. These signals are likely to involve PI3K and intracellular calcium stores since PI3K or SERCA pump inhibitors can phenocopy polycystin loss of function. Specifically, our findings that developmental collagen expression persists abnormally in older larvae lacking polycystins is directly relevant to defects associated with extracellular matrix seen in a variety of ADPKD pathologies including cystic kidney disease, vascular aneurysm, abdominal wall hernia, pericardial effusion, and defects in chondrogenesis. In this proposal we plan to exploit our ability to generate compound loss of function as well as gain of function conditions in zebrafish embryos to dissect signaling pathways by which polycystins function as sensors of the cellular environment. We hypothesize that Polycystin1, functioning at sites of cell matrix contact, interacts with focal adhesion proteins to generate signals involving PI3K that downregulate collagen gene expression. We will test whether beta1 integrin, FAK, or ILK are required in this pathway. We will also test whether the C-terminal product of Polycystin1 GPS cleavage or other subdomains of polycystin1 are sufficient to rescue polycystin1 morphants. The role of ER calcium stores in signaling will be explored by measuring ER calcium in polycystin deficient embryos and assaying for genetic interactions of polycystin1 and polycystin2 with stim1 and orai1, the recently discovered store operated calcium channels. Although it has long been appreciated that defects in extracellular matrix were prominent in ADPKD pathology, a direct role for Polycystins as regulators of matrix production has yet to be demonstrated. If sucessful, our work will provide a direct link between Polycystins as signaling proteins and the control of extracellular matrix production that may be common to all ADPKD pathologies.

Public Health Relevance

Polycystic kidney disease is a common life-threatening disorder for which there is no cure. We intend to show how mutations in Polycystic kidney disease genes result in structural defects in affected organs by causing misregulation of collagen gene expression. Understanding the cellular basis of this disease will create new opportunities to improve the lives of those that suffer from it.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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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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Massachusetts General Hospital
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