View of Epithelial Cell Polarity in a Single-Cell 9

EDITORIALS www.jasn.org

2. Stark K, Vainio S, Vassileva G, McMahon AP: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Polarity and Renal Cystogenesis Wnt-4. Nature 372: 679–683, 1994 3. Yu J, Carroll TJ, Rajagopal J, Kobayashi A, Ren Q, McMahon AP: A Gregory R. Dressler Wnt7b-dependent pathway regulates the orientation of epithelial cell Department of Pathology, University of Michigan, Ann Arbor, division and establishes the cortico-medullary axis of the mammalian Michigan kidney. Development 136: 161–171, 2009 4. Kuure S, Popsueva A, Jakobson M, Sainio K, Sariola H: Glycogen synthase J Am Soc Nephrol 23: 4–5, 2012. kinase-3 inactivation and stabilization of beta-catenin induce nephron doi: 10.1681/ASN.2011111121 differentiation in isolated mouse and rat kidney mesenchymes. JAm Soc Nephrol 18: 1130–1139, 2007 5. Park J-S, Valerius MT, McMahon AP: Wnt/beta-catenin signaling reg- Epithelial cells are the building blocks of segmenting renal ulates nephron induction during mouse kidney development. De- tubules.1 As such, there is great interest in how the differenti- velopment 134: 2533–2539, 2007 ation, proliferation, and organization of epithelial cells into 6. Bridgewater D, Cox B, Cain J, Lau A, Athaide V, Gill P, Kuure S, Sainio K, functional proximal, distal, and collecting tubules are con- Rosenblum N: Canonical WNT/beta-catenin signaling is required for ureteric branching. Dev Biol 317: 83–94, 2008 trolled at the genetic and cellular level. One of the most critical 7. Bridgewater D, Di Giovanni V, Cain JE, Cox B, Jakobson M, Sainio K, aspects of epithelial cell biology is the establishment and main- Rosenblum ND: b-catenin causes renal dysplasia via upregulation of tenanceofpolarity,whichissimplydefined as the unequal Tgfb2andDkk1.J Am Soc Nephrol 22: 718–731, 2011 distribution of cellular components along an axis in the service 8. Liu M, Shi S, Senthilnathan S, Yu J, Wu E, Bergmann C, Zerres K, of functionality. Loss of epithelial cell polarity is a common BogdanovaN,CotoE,DeltasC,PieridesA,DemetriouK,DevuystO, Gitomer B, Laakso M, Lumiaho A, LamnissouK,MagistroniR,Parfrey thread among the many types of juvenile and adult cystic dis- P, Breuning M, Peters DJ, Torra R, Winearls CG, Torres VE, Harris PC, eases of the kidneys and other tissues. Thus, understanding the Paterson AD, Pei Y: Genetic variation of DKK3 may modify molecular mechanisms that lead to the loss of epithelial cell renal disease severity in ADPKD. JAmSocNephrol21: 1510–1520, polarity has great clinical relevance. 2010 The common view of epithelial cell polarity in a single-cell 9. Grouls S, Iglesias DM, Wentzensen N, Moeller MJ, Bouchard M, Kemler R, Goodyer P, Niggli F, Gröne H-J, Kriz W, Koesters R: Lineage speci- columnar epithelium, such as a renal tubule, is organization of fication of parietal epithelial cells requires b-catenin/Wnt signaling. the cell into apical and basolateral compartments. However, JAmSocNephrol23: 63–72, 2012 there is a second aspect of polarity that requires the correct 10. Iglesias DM, Hueber P-A, Chu L, Campbell R, Patenaude A-M, orientation of individual cells along the plane of an epithelial Dziarmaga AJ, Quinlan J, Mohamed O, Dufort D, Goodyer PR: Ca- sheet or tube and is often critical for proper function. This macro nonical WNT signaling during kidney development. Am J Physiol Renal Physiol 293: F494–F500, 2007 view of polarity is called planar cell polarity, or sometimes just 11. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, planar polarity, and is found in tissues where all cells are Kriz W, Floege J, Moeller MJ: Recruitment of podocytes from glo- orientated in a specific direction along the plane of the tissue.2 merular parietal epithelial cells. JAmSocNephrol20: 333–343, Both apical-basal polarity and planar cell polarity have been 2009 extensively studied in the kidney and in other tissues of model 12. Lasagni L, Romagnani P: Glomerular epithelial stem cells: The good, the bad, and the ugly. JAmSocNephrol21: 1612–1619, organisms, as well as in human disease. Progress in identifying 2010 the many genes and proteins responsible for establishing po- 13. Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, larity and maintaining function has been remarkable, al- Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli though the interplay between the many different pathways is GB, Lasagni L, Romagnani S, Romagnani P: Regeneration of glomerular – still unclear. podocytes by human renal progenitors. J Am Soc Nephrol 20: 322 fi 332, 2009 One of the rst indications that apical-basal polarity was 14. Wang D, Dai C, Li Y, Liu Y: Canonical Wnt/b-catenin signaling mediates disturbed in renal cystic epithelial cells was the observation that 1 1 transforming growth factor-b1-driven podocyte injury and proteinuria. the Na /K -ATPase was mislocalized in cells from autosomal Kidney Int 80: 1159–1169, 2011 dominant polycystic kidney disease kidneys.3 Today, the idea 15. Reya T, Clevers H: Wnt signalling in stem cells and cancer. Nature 434: that disrupted apical-basal polarity drives cystogenesis 843–850, 2005 16. Barolo S: Transgenic Wnt/TCF pathway reporters: All you need is Lef? through a combination of apically mislocalized growth factor Oncogene 25: 7505–7511, 2006 receptors that promote proliferation and mislocalized ion 17. Lin S-L, Li B, Rao S, Yeo E-J, Hudson TE, Nowlin BT, Pei H, Chen L, channels that reverse fluid flow is still an attractive model to Zheng JJ, Carroll TJ, Pollard JW, McMahon AP, Lang RA, Duffield JS: explain many aspect of cystic disease.4 However, it is not clear Macrophage Wnt7b is critical for kidney repair and regeneration. Proc how this loss of apical-basal polarity occurs, nor how the Natl Acad Sci USA 107: 4194–4199, 2010 18. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM: Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479: 232– Published online ahead of print. Publication date available at www.jasn.org. 236, 2011 Correspondence: Dr. Gregory R. Dressler, Department of Pathology, 2049 BSRB 2200, University of Michigan, Ann Arbor, MI 48109. Email: dressler@ umich.edu See related article, “Lineage Specification of Parietal Epithelial Cells Requires b-Catenin/Wnt Signaling,” on pages 63–72. Copyright © 2012 by the American Society of Nephrology

4 Journal of the American Society of Nephrology J Am Soc Nephrol 23: 3–12, 2012 www.jasn.org EDITORIALS primary genes and proteins mutated in human polycystic kid- seems likely that establishing apical-basal polarity is a prereq- ney disease, the polycystins PC1 and PC2, affect apical-basal uisite for all other aspects of epithelial cell function, including polarity. proper localization of cilia and planar polarity. In certain cases, Within the last 5 years, several major discoveries have shifted it appears that planar polarity may provide some feedback to the emphasis onto the planar cell polarity pathway as a deter- maintain apical-basal polarity. How this is achieved remains minant of renal cystic disease.5 Central to understanding the unclear, but certainly provides for many avenues of further potential role of the planar cell polarity is the function of the investigation. primary cilia, in which nearly all of the proteins associated with cystic disease can be localized.6 Loss or shortening of cilia can be sufficient to initiate renal cysts, underscoring the importance of the cilia as a potential sensing and signaling center. Furthermore, DISCLOSURES primary cilia have been linked directly to planar polarity, par- None. ticularly in the cilia that control left-right asymmetry shortly after gastrulation.7 Uniform orientation of the primary cilia REFERENCES and synchronized movement is critical for the presumptive establishment of the morphogenetic gradients that specify left- 1. Kopan R, Cheng HT, Surendran K: Molecular insights into segmentation right asymmetry. along the proximal-distal axis of the nephron. JAmSocNephrol18: – The basal body of the primary cilia also functions as the 2014 2020, 2007 2. McNeill H: Planar cell polarity and the kidney. JAmSocNephrol20: centrosome, which on duplication during mitosis, anchors the 2104–2111, 2009 mitotic spindles and thus can control the axis of cell division. 3. Wilson PD, Sherwood AC, Palla K, Du J, Watson R, Norman JT: Re- Both PC1 and PC2 have been associated with the centrosome versed polarity of Na(1)-K(1) -ATPase: Mislocation to apical plasma and the mitotic spindles,8 with supernumerary centrosomes membranes in polycystic kidney disease epithelia. Am J Physiol 260: – observed on deletion of either protein. Thus, the orientation F420 F430, 1991 4. Wilson PD: Apico-basal polarity in polycystic kidney disease epithelia. of cell division along the axis of an epithelial tube was thought Biochim Biophys Acta 1812: 1239–1248, 2011 to be directly dependent on the cilia position and function and 5. Luyten A, Su X, Gondela S, Chen Y, Rompani S, Takakura A, Zhou J: determined, at least in part, by planar cell polarity. The axis of Aberrant regulation of planar cell polarity in polycystic kidney disease. cell division could determine whether an epithelial tube elon- J Am Soc Nephrol 21: 1521–1532, 2010 gates or whether it forms a cyst. Indeed, through careful anal- 6. Harris PC: 2008 Homer W. Smith Award: Insights into the pathogenesis of polycystic kidney disease from gene discovery. J Am Soc Nephrol 20: ysis of mitoses in several mutant mouse lines with developing 1188–1198, 2009 renal cysts, including Wnt9b,9 HNF1b,10 and Pkhd1,11 the 7. Wallingford JB, Mitchell B: Strange as it may seem: The many links orientation of cell division is random, whereas normally the between Wnt signaling, planar cell polarity, and cilia. Genes Dev 25: separation between two cells is perpendicular to the tubule, 201–213, 2011 suggesting this randomization is an underlying cause of cysto- 8. Battini L, Macip S, Fedorova E, Dikman S, Somlo S, Montagna C, Gusella GL: Loss of polycystin-1 causes centrosome amplifica- genesis. However, the axis of cell division does not appear tion and genomic instability. Hum Mol Genet 17: 2819–2833, affected in mice with PKD1 or PKD2 mutations, at least not 2008 until cysts are already formed, suggesting that misorientated 9. Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, Carroll cell division may not be necessary or sufficient for renal cyst TJ: Wnt9b signaling regulates planar cell polarity and kidney tubule – development.12 morphogenesis. Nat Genet 41: 793 799, 2009 10. Verdeguer F, Le Corre S, Fischer E, Callens C, Garbay S, Doyen A, et al.13 In this issue, Veikkolainen observe epithelial polarity Igarashi P, Terzi F, Pontoglio M: A mitotic transcriptional switch in defects in mice that carry either gain or loss-of-function muta- polycystic kidney disease. Nat Med 16: 106–110, 2009 tions in the receptor tyrosine kinase ErbB4. Members of the EGF 11. Fischer E, Legue E, Doyen A, Nato F, Nicolas JF, Torres V, Yaniv M, family of receptors, the ErbB proteins have been implicated as Pontoglio M: Defective planar cell polarity in polycystic kidney disease. – modulators of polarity in neurons and cancer. For example, Nat Genet 38: 21 23, 2006 12. Nishio S, Tian X, Gallagher AR, Yu Z, Patel V, Igarashi P, Somlo S: Loss of activation of the ErbB2 protein disrupts the apical-basal oriented cell division does not initiate cyst formation. J Am Soc Nephrol Par3-Par6-aPKC polarity complex, which is needed for tight 21: 295–302, 2010 junction assembly.14 The ErbB4 study in the kidney suggests 13. Veikkolainen V, Naillat F, Railo A, Chi L, Manninen A, Hohenstein P, that a similar type of apical-basal polarity disruption may be Hastie N, Vainio S, Elenius K: ErbB4 modulates tubular cell polarity and occurring here. That the activated ErbB4 mice develop cysts lumen diameter during kidney development. JAmSocNephrol23: 112–122, 2012 and also show misorientation of the cell division axis suggests 14. Aranda V, Haire T, Nolan ME, Calarco JP, Rosenberg AZ, Fawcett JP, that loss of apical-basal polarity is sufficient to explain the phe- Pawson T, Muthuswamy SK: Par6-aPKC uncouples ErbB2 induced nomena attributed, at least in part, to planar cell polarity path- disruption of polarized epithelial organization from proliferation con- ways in other cystic mutants. trol. Nat Cell Biol 8: 1235–1245, 2006 Renal epithelial cells are derived from the metanephric mesenchyme and are unique in that they must undergo a See related article, “ErbB4 Modulates Tubular Cell Polarity and Lumen Di- mesenchymal-to-epithelial transition during development. It ameter during Kidney Development,” on pages 112–122.

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