title: Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.
abstract: A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a 'truncation mutation' in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate 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.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.forename: A
authors.initials: A
authors.lastname: Pavlova
authors.forename: M
authors.initials: M
authors.lastname: Lakkis
authors.forename: C J
authors.initials: CJ
authors.lastname: Ward
authors.forename: L
authors.initials: L
authors.lastname: Pritchard
authors.forename: P C
authors.initials: PC
authors.lastname: Harris
authors.forename: D R
authors.initials: DR
authors.lastname: Genest
authors.forename: A R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: J
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000150:complications / Q000235:genetics*; D018450:Disease Progression; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D015160:Hydrops Fetalis / Q000150:complications; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation; D010181:Pancreatic Cyst / Q000150:complications; D010182:Pancreatic Diseases / Q000150:complications; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000235:genetics*; D006831:Polyhydramnios / Q000150:complications; D011247:Pregnancy; D011506:Proteins / Q000235:genetics*; D050396:TRPP Cation Channels
chemical_list: D011506:Proteins; D050396:TRPP Cation Channels