Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cy st formation in the kidney, liver, and pancreas and is associated often wit h cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, enc oding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2-/- mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1(del34) -/- and Pkd1(L) -/- mice have cysts but no cardiac abnormalities, although vascular fragility was re ported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1(del17-21 beta geo)), which defines its expression pattern by us ing a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1(del17-21 beta geo) +/- adult mice develop renal and hepatic cysts, Pkd1(del17-21 beta geo) +/- embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ven tricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities corr elate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 i s expressed in maturing tubular epithelial cells from embryonic day 15.5. T his expression coincides with the onset of cyst formation in Pkd1(del34) -/ -, Pkd1(L) -/-, and Pkd(2) -/- mice, supporting the hypothesis that polycys tin-1 and polycystin-2 interact in vivo and that their failure to do so lea ds to abnormalities in tubule morphology and function.