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Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation

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Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation BASIC RESEARCH www.jasn.org Lats1/2 Regulate Yap/Taz to Control Nephron Progenitor Epithelialization and Inhibit Myofibroblast Formation † † Helen McNeill* and Antoine Reginensi *Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; and †Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada 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 differentia- tion 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 of Lats1 and Lats2 in 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 and a-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 of Yap and/or Taz expression levels completely rescued the Lats1/2 phenotype. Taken together, our results demonstrate that Lats1/2 kinases restrict Yap/Taz activities to promote nephron progenitor cell differentiation in the mamma- lian kidney. Notably, our data also show that myofibroblastic cells can differentiate from nephron progenitors. J Am Soc Nephrol 28: ccc–ccc, 2016. doi: 10.1681/ASN.2016060611 Kidney organogenesis is a remarkably orchestrated, during embryonic development and have been im- reiteratedprocessthatdependsonreciprocalsignaling plicated in the growth of metastatic tumors.8 During between the epithelial ureteric bud (UB) and the MET, mesenchymal cells alter their shape and motile surrounding condensing mesenchyme (CM).1–4 Sig- behavior as they differentiate into epithelial cells by naling from the mesenchyme induces successive acquiring an apical-basal polarity, a basement mem- rounds of UB branching, generating the collecting brane, and adhesion with neighboring cells. Such duct (CD) of the kidney. Surrounding the UB are events of cellular transition and movements were un- self-renewing mesenchymal progenitor cells (called covered by means of lineage-tracing experiments in the CM or nephron progenitor cells [NPCs]) that express Six2 and Cited1.5,6 A subset of CM cells is reciprocally induced by the UB to form a pretubular Received June 2, 2016. Accepted August 2, 2016. aggregate (PA), which subsequently undergoes Published online ahead of print. Publication date available at mesenchymal-to-epithelial transition (MET) to www.jasn.org. form the renal vesicle (RV). The RV will then undergo Correspondence: Dr. Helen McNeill or Dr. Antoine Reginensi, morphogenesis to form the comma-shaped body Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, (CSB), followed by the S-shaped body (SSB) that 600 University Avenue, Room 881, Toronto, ON, M5G 1X5, will elongate to form the nephron.7 Both MET and Canada. Email: [email protected] or [email protected] epithelial-to-mesenchymal transition are essential Copyright © 2016 by the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc, 2016 ISSN : 1046-6673/2803-ccc 1 BASIC RESEARCH www.jasn.org the developing kidney using, among others, the Hoxb7 (UB), medullary regions (Figure 1, D–I). In control kidneys, higher Six2 (CM), and Foxd1-reporter models that label the CDs, neph- magnification views identified an active nephrogenic zone, a rons, and stromal derivatives, respectively.9–11 cortex with numerous glomeruli, proximal and distal tubules, The Hippo pathway is a conserved kinase cassette that and a medulla filled with stromal cells and CDs. Remarkably, 2 2 controls tissue growth through the activities of the Yap and Taz neither glomeruli nor tubules were observed in Lats1/2CM / effectors in both flies and mammals.12–14 These closely related kidneys at E18.5, and both the cortex and the medulla showed transcriptional coactivators promote the expression of pro- an accumulation of cells in the interstitium with a dense, proliferative and antiapoptotic genes. Upstream of Yap and glycoprotein-rich (periodic acid–Schiff [PAS]-positive) extra- Taz are the Hippo kinases Mst1/2 and Lats1/2, which nega- cellular matrix, surrounded by dense stroma (Figure 1, F–I). tively regulate Yap and Taz by causing their exclusion from the CM2/2 nuclear compartment. Loss of Hippo signaling (Mst1/2 or Accumulation of NP-Derived Cells in the Lats1/2 Lats1/2 inactivation) leads to unrestricted nuclear accumula- Kidney tion of Yap and Taz and has been linked to a variety of de- Nephrogenesis occurs in a repetitive manner, with new velopmental abnormalities and cancers.15–17 nephrons being formed throughout development in the In the developing mammalian kidney, Yap and Taz play nephrogenic zone. NPCs surrounding the UB tips concurrently different roles: Yap promotes nephron formation within the self-renew to replenish the pool of NPCs and undergo MET to NPC population18 and Taz prevents renal cyst formation.19,20 form early nephrons. To determine whether cells that accu- 2 2 Yap and Taz are also essential in the UB lineage for lower mulate in Lats1/2CM / kidney interstitium were derived from urinary tract development21 and branching morphogene- the NPCs, we performed lineage-tracing experiments using the sis.22 Finally, increased Yap and Taz have also been found to Rosa-mTomato/mGFP reporter mouse line (mTmG24) which, correlate with kidney fibrosis, using a unilateral ureteral ob- combined with the Six2:Cre system, produces a membrane- struction model.23 From these published data, it is clear that bound green fluorescent protein (GFP) that permanently labels loss of Yap and Taz are detrimental to kidney development and the NPCs and their daughter cells. We generated double con- fl fl function in the adult. However, the roles of the core Hippo ditional knockout Six2:Cre Lats1/2 ox/ ox mTmG mice, wherein fl kinases in NPCs remain to be investigated. compound mutants (Six2:Cre Lats1/2 ox/+ mTmG–double het- fl fl fl Here we uncover a role for the Hippo kinases, Lats1 and erozygous knockout, Six2:Cre Lats1 ox/+ Lats2 ox/ ox mTmG,and fl fl fl fl fl Lats2, in nephron progenitor (NP) differentiation and dem- Six2:Cre Lats1 ox/ ox Lats2 ox/+ mTmG) and Lats1/2 ox/ ox onstrate that Lats1 and Lats2 activities are critical during neph- mTmG (no Cre) were used as controls. We performed GFP ron formation. Removal of Lats1/2 from NPCs causes loss of and calbindin staining to mark the NPCs and daughter cells, nephron formation, accompanied with a change in cell fate and and the UB compartment, respectively, at E18.5. As expected, accumulation of myofibroblasts. The interstitial myofibroblas- no GFP staining was observed in any Cre controls (Figure 2A). tic cells also show high nuclear Yap and Taz accumulation with In both double heterozygous knockout animals and mutants loss of phospho-Yap. Remarkably, the conditional loss of Lats1/ with loss of three out of four Lats alleles, we observed GFP 2 in the NPC population is successfully rescued by depletion of expression in all NPCs throughout the nephrogenic zone and Yap and/or Taz. Taken together, these data demonstrate an es- in their epithelial descendants (both early and more mature sential role for the core Hippo kinases (Lats1 and Lats2) in nephrons [Figure 2, B and C, and higher magnification in Fig- restricting Yap/Taz activity during the self-renewal of NPCs ure 2E]). Thus, loss of three out of the four Lats alleles does not and MET and nephron formation in the mammalian kidney. affect nephrogenesis (Figure 2C). In contrast, nephrogenesis 2 2 does not occur in Lats1/2CM / kidneys, and all cells that ac- 2 2 cumulate in the Lats1/2CM / interstitium are GFP-positive, RESULTS indicating that they were derived from the NPCs (Figure 2, D and F). Lats1 and Lats2 Dual Deletion Results in Loss of Nephrogenesis Lats1/2 Deletion Impaired Maintenance and To investigate the role of Lats1 and Lats2 kinases in NPCs, both Differentiation of NPCs genes were conditionally inactivated using the Six2:CreTGC/+ To determine the developmental origin of the abnormal 2 2 allele.10 This system depletes Lats1 and Lats2 expression from nephrogenesis observed in Lats1/2CM / kidneys, we exam- fl fl NPCs and their epithelial derivatives. Six2:CreTGC/+ Lats1 ox/ ox ined earlier time points. In E14.5 control kidneys, 2–3 layers of fl fl 2 2 Lats2 ox/ ox (called Lats1/2CM / ) mice died within 24 hours Six2-positive self-renewing NPCs surround the dorsal side of after birth. Gross anatomic examination revealed that embry- the UB, with early nephron structures (PA, RV, CSB and SSB) 2 2 onic day 18.5 (E18.5) Lats1/2CM / embryos had a dramatic forming on the ventral side of the UB. Six2 immunofluores- 2 2 decrease in kidney size compared with controls (Lats1/2CM / : cence (Figure 3, A–G) and lineage tracing (Figure 2F) 2.360.1 mm2, n=6; controls: 4.560.2 mm2, n=8; Figure 1, revealed a reduced pool of Six2-positive cells capping UB A–C). Histologic examination of E18.5 kidneys revealed loss of tips (quantification in Figure 3G), indicating that Lats1/2 de- nephrogenesis and accumulation of cells in both cortical and letion leads to poor maintenance of the NPCs. Moreover, 2 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc,2016 www.jasn.org BASIC RESEARCH Figure 1.
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