title: Different effects of ZO-1, ZO-2 and ZO-3 silencing on kidney collecting duct principal cell proliferation and adhesion.
abstract: Coordinated cell proliferation and ability to form intercellular seals are essential features of epithelial tissue function. Tight junctions (TJs) classically act as paracellular diffusion barriers. More recently, their role in regulating epithelial cell proliferation in conjunction with scaffolding zonula occludens (ZO) proteins has come to light. The kidney collecting duct (CD) is a model of tight epithelium that displays intense proliferation during embryogenesis followed by very low cell turnover in the adult kidney. Here, we examined the influence of each ZO protein (ZO-1, -2 and -3) on CD cell proliferation. We show that all 3 ZO proteins are strongly expressed in native CD and are present at both intercellular junctions and nuclei of cultured CD principal cells (mCCDcl1). Suppression of either ZO-1 or ZO-2 resulted in increased G0/G1 retention in mCCDcl1 cells. ZO-2 suppression decreased cyclin D1 abundance while ZO-1 suppression was accompanied by increased nuclear p21 localization, the depletion of which restored cell cycle progression. Contrary to ZO-1 and ZO-2, ZO-3 expression at intercellular junctions dramatically increased with cell density and relied on the presence of ZO-1. ZO-3 depletion did not affect cell cycle progression but increased cell detachment. This latter event partly relied on increased nuclear cyclin D1 abundance and was associated with altered β1-integrin subcellular distribution and decreased occludin expression at intercellular junctions. These data reveal diverging, but interconnected, roles for each ZO protein in mCCDcl1 proliferation. While ZO-1 and ZO-2 participate in cell cycle progression, ZO-3 is an important component of cell adhesion.
authors.affiliation: a Department of Cellular Physiology and Metabolism and Service of Nephrology ; University Medical Center; University of Geneva ; Geneva , Switzerland.
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Qiao
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roth
authors.forename: Eric
authors.initials: E
authors.lastname: Féraille
authors.forename: Udo
authors.initials: U
authors.lastname: Hasler
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000166:cytology* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D062825:Zonula Occludens Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D062827:Zonula Occludens-2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D062825:Zonula Occludens Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; D019938:Cyclin D1
keywords: CCD, cortical collecting duct; CD, collecting duct; CycD1, cyclin D1; OMCD, outer medullary collecting duct; PCNA, proliferating cell nuclear antigen; PCT, proximal tubule; TAL, thick ascending limb of Henle's loop; TJ, tight junction; ZO, zonula occludens; ZONAB; ZONAB, ZO-1-associated nucleic acid-binding protein; adhesion; cell cycle; cyclin D1; kidney collecting duct; p21; proliferation; zonula occludens