Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects

A high level of polycystin-1 expression is detected in kidneys of all patie nts with autosomal dominant polycystic kidney disease (ADPKD). Mice that ov erexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cysts formation is still unclear. Here, we re port the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotype characterization in comparison with the del34 mutants th at carry a 'truncation mutation' in Pkd1. We show that null homozygotes dev elop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygotes mutants develop poly hydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia . Heterozygotes also develop adult-onset pancreatic disease. We show furthe r that del34 homozygotes continue to produce mutant polycystin-1, thereby p roviding a possible explanation for increased immunoreactive polycystin-1 i n ADPKD cyst epithelia in the context of the two-hit model. Our data demons trate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.