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Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation
W Lu1, B Peissel, H Babakhanlou
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Insights
Mutations in PKD1 cause autosomal dominant polycystic kidney disease (ADPKD). A Pkd1 mutation in mice caused severe cystic kidneys and organ development defects, indicating polycystin
Area of Science:
- Genetics
- Developmental Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by progressive kidney cyst formation and eventual renal failure.
- The PKD1 gene encodes polycystin, a cell-surface protein crucial for epithelial development, but its precise function remains largely unknown.
- Existing mouse models do not fully replicate the genetic basis or pathology of human ADPKD.
Purpose of the Study:
- To investigate the function of the PKD1 protein in kidney and pancreas development.
- To create and characterize a mouse model mimicking human ADPKD-associated PKD1 mutations.
Main Methods:
- Homologous recombination was used to introduce a Pkd1 truncation mutation (Pkd1-) into mouse embryonic stem cells.
- The resulting Pkd1- mutant mice were analyzed for phenotypic abnormalities, focusing on kidney, pancreas, and lung development.
- Histological analysis was performed to determine the timing and extent of cyst formation during embryonic development.
Main Results:
- Pkd1- homozygotes exhibited perinatal lethality with severely enlarged, cystic kidneys, pancreatic ductal cysts, and pulmonary hypoplasia.
- Renal cystogenesis initiated at embryonic day 15.5 in proximal tubules and rapidly affected the entire kidney parenchyma.
- Pkd1- heterozygotes showed no discernible phenotype, suggesting a critical role for full-length polycystin dosage.
Conclusions:
- The Pkd1- mouse model effectively recapitulates key features of human ADPKD, including early-onset cyst formation.
- Full-length polycystin is essential for normal kidney and pancreas morphogenesis, particularly during tubular development and elongation.
- This study provides critical insights into the molecular mechanisms underlying polycystic kidney disease and polycystin function.
Abstract:
PKD1 is the most common site for mutations in human autosomal dominant polycystic kidney disease (ADPKD). ADPKD is characterized by progressive replacement of kidney tissue by epithelial cysts and eventual renal failure. Hepatic and pancreatic cysts are also common. The PKD1 protein, polycystin, is a cell-surface protein of unknown function that is widely expressed in epithelia and in vascular smooth muscle and myocardium. None of the genetic forms of murine polycystic disease map to the murine Pkd1 locus. We introduced into mice by homologous recombination a Pkd1 truncation mutation, Pkd1-, that mimics a mutation found in ADPKD. Pkd1- heterozygotes have no discernible phenotype, whereas homozygotes die during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts and pulmonary hypoplasia. Renal cyst formation begins at embryonic day 15.5 (E15.5) in proximal tubules and progresses rapidly to replace the entire renal parenchyma. The timing of cyst formation indicates that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas.