Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease occurring at a frequency of 1:1000 in humans and characterized by cyst formation in kidney tubules, deregulated fluid transport and alteration of extracellular adhesion. ADPKD is caused by mutations in the PKD1 or PKD2 gene that encode polycystin-1 and polycystin-2, respectively. The primary causes and mechanisms of cyst formation in ADPKD remain elusive. Our attempts to knockdown pkdl in zebrafish failed because of gene redundancy. Medaka is a unique inbred aquatic vertebrate fish model system, which shows lower redundancy in gene number compared to zebrafish. The use of medaka provides an opportunity to develop a novel system to study organogenesis and to understand the mechanisms of cystogenesis. Given that PKD1 mutations account for 85% of all ADPKD cases in humans, we have targeted pkdl in medaka to understand its function(s). Preliminary results demonstrate that targeting pkdl in medaka (in contrast to zebrafish) causes prronephric cysts formation. We have also established a system using medaka for studies of kidney, cystogenesis that is sensitive for the defect of polycystin-1 interacting proteins such as polycystin-2, which can be used to assess the in vivo relevance of the large number of polycystin-1 interacting proteins.
In specific aim 1, we will test the in vivo function of specific polycystin-1 motifs by disrupting pkdl mRNA splicing and generate an allelic series of deletions in medaka. For this purpose, we propose to use our urogenital specific medaka transgenic GFP line to monitor the progress of cyst formation, and to analyze the kidney phenotypes as well as other potential defects in organogenesis caused by the defers.
In specific aim 2, we will validate the biological significance of polycystin-1 interacting proteins.
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