期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 47, 页码 18688-18693出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708217104
关键词
autosomal dominant polycystic kidney disease; cis-autoproteolytic cleavage; GPS; knockin mouse; tubulogenesis
资金
- NCI NIH HHS [P30 CA021765, CA21765] Funding Source: Medline
- NIDCD NIH HHS [DC06471, R01 DC006471] Funding Source: Medline
- NIDDK NIH HHS [R01 DK051259, DK062199, DK48006, R37 DK048006, DK51259, R01 DK062199, R01 DK048006] Funding Source: Medline
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 wildtype 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.
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