Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin.
Loss of polycystin-2 (PC2) in mice (Pkd2(-/-)) results in total body edema, focal hemorrhage, structural cardiac defects, abnormal left-right axis, hepatorenal and pancreatic cysts, and embryonic lethality. The molecular mechanisms by which loss of PC2 leads to these phenotypes remain unknown. We generated a model to allow targeted Pkd2 inactivation using the Cre-loxP system. Global inactivation of Pkd2 produced a phenotype identical to Pkd2(-/-) mice with undetectable PC2 protein and perinatal lethality. Using various Cre mouse lines, we found that kidney, pancreas, or time-specific deletion of Pkd2 led to cyst formation. In addition, we developed an immortalized renal collecting duct cell line with inactive Pkd2; these cells had aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis. They also significantly upregulated beta-catenin, axin2, and cMyc. Our results suggest that loss of PC2 disrupts normal behavior of renal epithelial cells through dysregulation of beta-catenin-dependent signaling, revealing a potential role for this signaling pathway in PC2-associated ADPKD.
Kim
Ingyu
I
Division of Genetic Medicine, Department of Medicine and Cell and Developmental Biology, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232, USA.
Ding
Tianbing
T
Fu
Yulong
Y
Li
Cunxi
C
Cui
Lan
L
Li
Ao
A
Lian
Peiwen
P
Liang
Dan
D
Wang
Dao W
DW
Guo
Caiying
C
Ma
Jie
J
Zhao
Ping
P
Coffey
Robert J
RJ
Zhan
Qimin
Q
Wu
Guanqing
G
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D003560:Cysts / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007685:Kidney Tubules, Collecting / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010182:Pancreatic Diseases / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
D050396:TRPP Cation Channels; D051176:beta Catenin; C495267:CTNNB1 protein, mouse