title: Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation.
abstract: In the kidney, formation of the functional filtration units, the nephrons, is essential for postnatal life. During development, mesenchymal progenitors tightly regulate the balance between self-renewal and differentiation to give rise to all nephron epithelia. Here, we investigated the functions of the Hippo pathway serine/threonine-protein kinases Lats1 and Lats2, which phosphorylate and inhibit the transcriptional coactivators Yap and Taz, in nephron progenitor cells. Genetic deletion ofLats1andLats2in nephron progenitors of mice led to disruption of nephrogenesis, with an accumulation of spindle-shaped cells in both cortical and medullary regions of the kidney. Lineage-tracing experiments revealed that the cells that accumulated in the interstitium derived from nephron progenitor cells and expressed E-cadherin as well as vimentin, a myofibroblastic marker not usually detected after mesenchymal-to-epithelial transition. The accumulation of these interstitial cells associated with collagen deposition and ectopic expression of the myofibroblastic markers vimentin andα-smooth-muscle actin in developing kidneys. Although these myofibroblastic cells had high Yap and Taz accumulation in the nucleus concomitant with a loss of phosphorylated Yap, reduction ofYapand/orTazexpression levels completely rescued theLats1/2phenotype. Taken together, our results demonstrate that Lats1/2 kinases restrict Yap/Taz activities to promote nephron progenitor cell differentiation in the mammalian kidney. Notably, our data also show that myofibroblastic cells can differentiate from nephron progenitors.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; and mcneill@lunenfeld.ca reginensi@lunenfeld.ca.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Antoine
authors.initials: A
authors.lastname: Reginensi
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D004848:Epithelium; D051379:Mice; D058628:Myofibroblasts / Q000502:physiology*; D009399:Nephrons / Q000166:cytology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; Lats1/2; MET; Myofibroblast; Yap/Taz; nephron