Abstract:
:In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently express cadherin-8 (cad8), and expression of cad8 ectopically in vitro suffices to initiate cystogenesis. To explore cell behavioral mechanisms of cad8-driven cyst initiation, we developed a virtual-tissue computer model. Our simulations predicted that either reduced cell-cell adhesion or reduced contact inhibition of proliferation triggers cyst induction. To reproduce the full range of cyst morphologies observed in vivo, changes in both cell adhesion and proliferation are required. However, only loss-of-adhesion simulations produced morphologies matching in vitro cad8-induced cysts. Conversely, the saccular cysts described by others arise predominantly by decreased contact inhibition, that is, increased proliferation. In vitro experiments confirmed that cell-cell adhesion was reduced and proliferation was increased by ectopic cad8 expression. We conclude that adhesion loss due to cadherin type switching in ADPKD suffices to drive cystogenesis. Thus, control of cadherin type switching provides a new target for therapeutic intervention.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Belmonte JM,Clendenon SG,Oliveira GM,Swat MH,Greene EV,Jeyaraman S,Glazier JA,Bacallao RLdoi
10.1091/mbc.E16-01-0059subject
Has Abstractpub_date
2016-11-07 00:00:00pages
3673-3685issue
22eissn
1059-1524issn
1939-4586pii
mbc.E16-01-0059journal_volume
27pub_type
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