TY - JOUR
T1 - Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects
AU - Lu, Weining
AU - Shen, Xiaohua
AU - Pavlova, Anna
AU - Lakkis, Montaha
AU - Ward, Christopher J.
AU - Pritchard, Lynn
AU - Harris, Peter C.
AU - Genest, David R.
AU - Perez-Atayde, Antonio R.
AU - Zhou, Jing
PY - 2001/11/1
Y1 - 2001/11/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/10.21.2385
DO - 10.1093/hmg/10.21.2385
M3 - Article
C2 - 11689485
AN - SCOPUS:0035504102
SN - 0964-6906
VL - 10
SP - 2385
EP - 2396
JO - Human molecular genetics
JF - Human molecular genetics
IS - 21
ER -