Abstract
Polycystin-1 (PC1) has an essential function in renal tubular morphogenesis and disruption of its function causes cystogenesis in human autosomal dominant polycystic kidney disease. We have previously shown that recombinant human PC1 is
cis
-autoproteolytically cleaved at the G protein-coupled receptor proteolytic site domain. To investigate the role of cleavage
in vivo
, we generated by gene targeting a
Pkd1
knockin mouse (
Pkd1
V/V
) that expresses noncleavable PC1. The
Pkd1
V/V
mice show a hypomorphic phenotype, characterized by a delayed onset and distal nephron segment involvement of cystogenesis at postnatal maturation stage. We show that PC1 is ubiquitously and incompletely cleaved in wild-type mice, so that uncleaved and cleaved PC1 molecules coexist. Our study establishes a critical but restricted role of cleavage for PC1 function and suggests a differential function of the two types of PC1 molecules
in vivo
.