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Functional roles of Grainyhead-like transcription factors in renal development and disease

  • Felix J. Boivin
  • Kai M. Schmidt-OttEmail author
Review

Abstract

Proper renal function relies on the tightly regulated development of nephrons and collecting ducts. This process, known as tubulogenesis, involves dynamic cellular and molecular changes that instruct cells to form highly organized tubes of epithelial cells which compartmentalize the renal interstitium and tubular lumen via assembly of a selective barrier. The integrity and diversity of the various renal epithelia is achieved via formation of intercellular protein complexes along the apical–basal axis of the epithelial cells. In recent years, the evolutionarily conserved family of Grainyhead-like (GRHL) transcription factors which encompasses three mammalian family members (Grainyhead-like 1, 2, 3) has emerged as a group of critical regulators for organ development, epithelial differentiation, and barrier formation. Evidence from transgenic animal models supports the presence of Grainyhead-like-dependent transcriptional mechanisms that promote formation and maintenance of epithelial barriers in the kidney. In this review, we highlight different Grhl-dependent mechanisms that modulate epithelial differentiation in the kidney. Additionally, we discuss how disruptions in these mechanisms result in impaired renal function later in life.

Keywords

Kidney development Urothelial development Kidney disease Grainyhead-like factors Epithelial barrier Epithelial morphogenesis Tight junctions 

Notes

Acknowledgments

This work was supported by the German Research Foundation (DFG) (FOR1368, GRK2318) and by the Urological Research Foundation (Stiftung Urologische Forschung, Berlin). F.J.B. was supported by a fellowship from the Alexander von Humboldt Foundation.

Compliance with ethical standards

Disclosures

No conflicts of interest, financial or otherwise, are declared by the authors.

References

  1. 1.
    Powell DW (1981) Barrier function of epithelia. Am J Phys 241:G275–G288Google Scholar
  2. 2.
    Denker BM, Sabath E (2011) The biology of epithelial cell tight junctions in the kidney. J Am Soc Nephrol 22:622–625CrossRefGoogle Scholar
  3. 3.
    Pawlak M, Walkowska A, Mlacki M, Pistolic J, Wrzesinski T, Benes V, Jane SM, Wesoly J, Kompanowska-Jezierska E, Wilanowski T (2015) Consequences of the loss of the Grainyhead-like 1 gene for renal gene expression, regulation of blood pressure and heart rate in a mouse model. Acta Biochim Pol 62:287–296CrossRefGoogle Scholar
  4. 4.
    Aue A, Hinze C, Walentin K, Ruffert J, Yurtdas Y, Werth M, Chen W, Rabien A, Kilic E, Schulzke JD, Schumann M, Schmidt-Ott KM (2015) A Grainyhead-like 2/Ovo-like 2 pathway regulates renal epithelial barrier function and lumen expansion. J Am Soc Nephrol 26:2704–2715CrossRefGoogle Scholar
  5. 5.
    Hinze C, Ruffert J, Walentin K, Himmerkus N, Nikpey E, Tenstad O, Wiig H, Mutig K, Yurtdas ZY, Klein JD, Sands JM, Branchi F, Schumann M, Bachmann S, Bleich M, Schmidt-Ott KM (2018) GRHL2 is required for collecting duct epithelial barrier function and renal osmoregulation. J Am Soc Nephrol 29:857–868PubMedGoogle Scholar
  6. 6.
    Yu Z, Mannik J, Soto A, Lin KK, Andersen B (2009) The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation. EMBO J 28:1890–1903CrossRefGoogle Scholar
  7. 7.
    Muto S (2017) Physiological roles of claudins in kidney tubule paracellular transport. Am J Physiol Renal Physiol 312:F9–F24CrossRefGoogle Scholar
  8. 8.
    Andrew DJ, Ewald AJ (2010) Morphogenesis of epithelial tubes: insights into tube formation, elongation, and elaboration. Dev Biol 341:34–55CrossRefGoogle Scholar
  9. 9.
    McMahon AP (2016) Development of the mammalian kidney. Curr Top Dev Biol 117:31–64CrossRefGoogle Scholar
  10. 10.
    Combes AN, Davies JA, Little MH (2015) Cell–cell interactions driving kidney morphogenesis. Curr Top Dev Biol 112:467–508CrossRefGoogle Scholar
  11. 11.
    Short KM, Combes AN, Lefevre J, Ju AL, Georgas KM, Lamberton T, Cairncross O, Rumballe BA, McMahon AP, Hamilton NA, Smyth IM, Little MH (2014) Global quantification of tissue dynamics in the developing mouse kidney. Dev Cell 29:188–202CrossRefGoogle Scholar
  12. 12.
    Lefevre JG, Short KM, Lamberton TO, Michos O, Graf D, Smyth IM, Hamilton NA (2017) Branching morphogenesis in the developing kidney is governed by rules that pattern the ureteric tree. Development 144:4377–4385CrossRefGoogle Scholar
  13. 13.
    Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP (2005) Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell 9:283–292CrossRefGoogle Scholar
  14. 14.
    Karner CM, Das A, Ma Z, Self M, Chen C, Lum L, Oliver G, Carroll TJ (2011) Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development 138:1247–1257CrossRefGoogle Scholar
  15. 15.
    Oxburgh L (2018) Kidney nephron determination. Annu Rev Cell Dev Biol 34:427–450CrossRefGoogle Scholar
  16. 16.
    Little MH, McMahon AP (2012) Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol 4:a008300Google Scholar
  17. 17.
    Schmidt-Ott KM, Masckauchan TN, Chen X, Hirsh BJ, Sarkar A, Yang J, Paragas N, Wallace VA, Dufort D, Pavlidis P, Jagla B, Kitajewski J, Barasch J (2007) Beta-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors. Development 134:3177–3190CrossRefGoogle Scholar
  18. 18.
    Boualia SK, Gaitan Y, Tremblay M, Sharma R, Cardin J, Kania A, Bouchard M (2013) A core transcriptional network composed of Pax2/8, Gata3 and Lim1 regulates key players of pro/mesonephros morphogenesis. Dev Biol 382:555–566CrossRefGoogle Scholar
  19. 19.
    Soofi A, Levitan I, Dressler GR (2012) Two novel EGFP insertion alleles reveal unique aspects of Pax2 function in embryonic and adult kidneys. Dev Biol 365:241–250CrossRefGoogle Scholar
  20. 20.
    Auden A, Caddy J, Wilanowski T, Ting SB, Cunningham JM, Jane SM (2006) Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development. Gene Expr Patterns 6:964–970CrossRefGoogle Scholar
  21. 21.
    Park J, Shrestha R, Qiu C, Kondo A, Huang S, Werth M, Li M, Barasch J, Susztak K (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758–763CrossRefGoogle Scholar
  22. 22.
    Jacobs J, Atkins M, Davie K, Imrichova H, Romanelli L, Christiaens V, Hulselmans G, Potier D, Wouters J, Taskiran II, Paciello G, Gonzalez-Blas CB, Koldere D, Aibar S, Halder G, Aerts S (2018) The transcription factor grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes. Nat Genet 50:1011–1020CrossRefGoogle Scholar
  23. 23.
    Chen AF, Liu AJ, Krishnakumar R, Freimer JW, DeVeale B, Blelloch R (2018) GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naive pluripotency. Cell Stem Cell 23:226–238 e224CrossRefGoogle Scholar
  24. 24.
    Martovetsky G, Tee JB, Nigam SK (2013) Hepatocyte nuclear factors 4alpha and 1alpha regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters. Mol Pharmacol 84:808–823CrossRefGoogle Scholar
  25. 25.
    Eeckhoute J, Formstecher P, Laine B (2004) Hepatocyte nuclear factor 4alpha enhances the hepatocyte nuclear factor 1alpha-mediated activation of transcription. Nucleic Acids Res 32:2586–2593CrossRefGoogle Scholar
  26. 26.
    Luk JM, Tong MK, Mok BW, Tam PC, Yeung WS, Lee KF (2004) Sp1 site is crucial for the mouse claudin-19 gene expression in the kidney cells. FEBS Lett 578:251–256CrossRefGoogle Scholar
  27. 27.
    Boivin FJ, Schmidt-Ott KM (2017) Transcriptional mechanisms coordinating tight junction assembly during epithelial differentiation. Ann N Y Acad Sci 1397:80–99CrossRefGoogle Scholar
  28. 28.
    Khan N, Asif AR (2015) Transcriptional regulators of claudins in epithelial tight junctions. Mediat Inflamm 2015:219843CrossRefGoogle Scholar
  29. 29.
    Gunzel D, Yu AS (2013) Claudins and the modulation of tight junction permeability. Physiol Rev 93:525–569CrossRefGoogle Scholar
  30. 30.
    Bray SJ, Kafatos FC (1991) Developmental function of Elf-1: an essential transcription factor during embryogenesis in Drosophila. Genes Dev 5:1672–1683CrossRefGoogle Scholar
  31. 31.
    Dynlacht BD, Attardi LD, Admon A, Freeman M, Tjian R (1989) Functional analysis of NTF-1, a developmentally regulated Drosophila transcription factor that binds neuronal cis elements. Genes Dev 3:1677–1688CrossRefGoogle Scholar
  32. 32.
    Wilanowski T, Caddy J, Ting SB, Hislop NR, Cerruti L, Auden A, Zhao LL, Asquith S, Ellis S, Sinclair R, Cunningham JM, Jane SM (2008) Perturbed desmosomal cadherin expression in grainy head-like 1-null mice. EMBO J 27:886–897CrossRefGoogle Scholar
  33. 33.
    Ting SB, Wilanowski T, Cerruti L, Zhao LL, Cunningham JM, Jane SM (2003) The identification and characterization of human sister-of-mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. Biochem J 370:953–962CrossRefGoogle Scholar
  34. 34.
    Kudryavtseva EI, Sugihara TM, Wang N, Lasso RJ, Gudnason JF, Lipkin SM, Andersen B (2003) Identification and characterization of Grainyhead-like epithelial transactivator (GET-1), a novel mammalian Grainyhead-like factor. Dev Dyn 226:604–617CrossRefGoogle Scholar
  35. 35.
    Traylor-Knowles N, Hansen U, Dubuc TQ, Martindale MQ, Kaufman L, Finnerty JR (2010) The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages. BMC Evol Biol 10:101CrossRefGoogle Scholar
  36. 36.
    Venkatesan K, McManus HR, Mello CC, Smith TF, Hansen U (2003) Functional conservation between members of an ancient duplicated transcription factor family, LSF/Grainyhead. Nucleic Acids Res 31:4304–4316CrossRefGoogle Scholar
  37. 37.
    Ting SB, Caddy J, Hislop N, Wilanowski T, Auden A, Zhao LL, Ellis S, Kaur P, Uchida Y, Holleran WM, Elias PM, Cunningham JM, Jane SM (2005) A homolog of Drosophila grainy head is essential for epidermal integrity in mice. Science 308:411–413CrossRefGoogle Scholar
  38. 38.
    Yu Z, Lin KK, Bhandari A, Spencer JA, Xu X, Wang N, Lu Z, Gill GN, Roop DR, Wertz P, Andersen B (2006) The Grainyhead-like epithelial transactivator get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Dev Biol 299:122–136CrossRefGoogle Scholar
  39. 39.
    Werth M, Walentin K, Aue A, Schonheit J, Wuebken A, Pode-Shakked N, Vilianovitch L, Erdmann B, Dekel B, Bader M, Barasch J, Rosenbauer F, Luft FC, Schmidt-Ott KM (2010) The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex. Development 137:3835–3845CrossRefGoogle Scholar
  40. 40.
    Ming Q, Roske Y, Schuetz A, Walentin K, Ibraimi I, Schmidt-Ott KM, Heinemann U (2018) Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family. Nucleic Acids Res 46:2082–2095CrossRefGoogle Scholar
  41. 41.
    Narasimha M, Uv A, Krejci A, Brown NH, Bray SJ (2008) Grainy head promotes expression of septate junction proteins and influences epithelial morphogenesis. J Cell Sci 121:747–752CrossRefGoogle Scholar
  42. 42.
    Carpinelli MR, de Vries ME, Jane SM, Dworkin S (2017) Grainyhead-like transcription factors in craniofacial development. J Dent Res 96:1200–1209CrossRefGoogle Scholar
  43. 43.
    Gustavsson P, Copp AJ, Greene ND (2008) Grainyhead genes and mammalian neural tube closure. Birth Defects Res A Clin Mol Teratol 82:728–735CrossRefGoogle Scholar
  44. 44.
    Kitazawa K, Hikichi T, Nakamura T, Mitsunaga K, Tanaka A, Nakamura M, Yamakawa T, Furukawa S, Takasaka M, Goshima N, Watanabe A, Okita K, Kawasaki S, Ueno M, Kinoshita S, Masui S (2016) OVOL2 maintains the transcriptional program of human corneal epithelium by suppressing epithelial-to-mesenchymal transition. Cell Rep 15:1359–1368CrossRefGoogle Scholar
  45. 45.
    Watanabe K, Villarreal-Ponce A, Sun P, Salmans ML, Fallahi M, Andersen B, Dai X (2014) Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell 29:59–74CrossRefGoogle Scholar
  46. 46.
    Mackay DR, Hu M, Li B, Rheaume C, Dai X (2006) The mouse Ovol2 gene is required for cranial neural tube development. Dev Biol 291:38–52CrossRefGoogle Scholar
  47. 47.
    Senga K, Mostov KE, Mitaka T, Miyajima A, Tanimizu N (2012) Grainyhead-like 2 regulates epithelial morphogenesis by establishing functional tight junctions through the organization of a molecular network among claudin3, claudin4, and Rab25. Mol Biol Cell 23:2845–2855CrossRefGoogle Scholar
  48. 48.
    Varma S, Cao Y, Tagne JB, Lakshminarayanan M, Li J, Friedman TB, Morell RJ, Warburton D, Kotton DN, Ramirez MI (2012) The transcription factors Grainyhead-like 2 and NK2-homeobox 1 form a regulatory loop that coordinates lung epithelial cell morphogenesis and differentiation. J Biol Chem 287:37282–37295CrossRefGoogle Scholar
  49. 49.
    Gao X, Vockley CM, Pauli F, Newberry KM, Xue Y, Randell SH, Reddy TE, Hogan BL (2013) Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium. [corrected]. Proc Natl Acad Sci U S A 110:9356–9361CrossRefGoogle Scholar
  50. 50.
    Negrete HO, Lavelle JP, Berg J, Lewis SA, Zeidel ML (1996) Permeability properties of the intact mammalian bladder epithelium. Am J Phys 271:F886–F894Google Scholar
  51. 51.
    McConnell BB, Ghaleb AM, Nandan MO, Yang VW (2007) The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology. Bioessays 29:549–557CrossRefGoogle Scholar
  52. 52.
    Bell SM, Zhang L, Mendell A, Xu Y, Haitchi HM, Lessard JL, Whitsett JA (2011) Kruppel-like factor 5 is required for formation and differentiation of the bladder urothelium. Dev Biol 358:79–90CrossRefGoogle Scholar
  53. 53.
    Wilanowski T, Tuckfield A, Cerruti L, O'Connell S, Saint R, Parekh V, Tao J, Cunningham JM, Jane SM (2002) A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead. Mech Dev 114:37–50CrossRefGoogle Scholar
  54. 54.
    Harris RC, Zhang MZ (2012) Dopamine, the kidney, and hypertension. Curr Hypertens Rep 14:138–143CrossRefGoogle Scholar
  55. 55.
    Yu P, Yang Z, Jones JE, Wang Z, Owens SA, Mueller SC, Felder RA, Jose PA (2004) D1 dopamine receptor signaling involves caveolin-2 in HEK-293 cells. Kidney Int 66:2167–2180CrossRefGoogle Scholar
  56. 56.
    Pyrgaki C, Liu A, Niswander L (2011) Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion. Dev Biol 353:38–49CrossRefGoogle Scholar
  57. 57.
    Brouns MR, De Castro SC, Terwindt-Rouwenhorst EA, Massa V, Hekking JW, Hirst CS, Savery D, Munts C, Partridge D, Lamers W, Kohler E, van Straaten HW, Copp AJ, Greene ND (2011) Over-expression of Grhl2 causes spina bifida in the axial defects mutant mouse. Hum Mol Genet 20:1536–1546CrossRefGoogle Scholar
  58. 58.
    Walentin K, Hinze C, Werth M, Haase N, Varma S, Morell R, Aue A, Potschke E, Warburton D, Qiu A, Barasch J, Purfurst B, Dieterich C, Popova E, Bader M, Dechend R, Staff AC, Yurtdas ZY, Kilic E, Schmidt-Ott KM (2015) A Grhl2-dependent gene network controls trophoblast branching morphogenesis. Development 142:1125–1136CrossRefGoogle Scholar
  59. 59.
    Ting SB, Wilanowski T, Auden A, Hall M, Voss AK, Thomas T, Parekh V, Cunningham JM, Jane SM (2003) Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3. Nat Med 9:1513–1519CrossRefGoogle Scholar
  60. 60.
    Walne AJ, Collopy L, Cardoso S, Ellison A, Plagnol V, Albayrak C, Albayrak D, Kilic SS, Patiroglu T, Akar H, Godfrey K, Carter T, Marafie M, Vora A, Sundin M, Vulliamy T, Tummala H, Dokal I (2016) Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis. Haematologica 101:1180–1189CrossRefGoogle Scholar
  61. 61.
    Balci S, Engiz O, Erekul A, Gozdasoglu S, Vulliamy T (2009) An atypical form of dyskeratosis congenita with renal agenesis and no mutation in DKC1, TERC and TERT genes. J Eur Acad Dermatol Venereol 23:607–608CrossRefGoogle Scholar
  62. 62.
    Liu KC, Cheney RE (2012) Myosins in cell junctions. Bioarchitecture 2:158–170CrossRefGoogle Scholar
  63. 63.
    Yeo NC, O'Meara CC, Bonomo JA, Veth KN, Tomar R, Flister MJ, Drummond IA, Bowden DW, Freedman BI, Lazar J, Link BA, Jacob HJ (2015) Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. Genome Res 25:57–65CrossRefGoogle Scholar
  64. 64.
    Qiao X, Roth I, Feraille E, Hasler U (2014) Different effects of ZO-1, ZO-2 and ZO-3 silencing on kidney collecting duct principal cell proliferation and adhesion. Cell Cycle 13:3059–3075CrossRefGoogle Scholar
  65. 65.
    Kurbel S, Dodig K, Radic R (2002) The osmotic gradient in kidney medulla: a retold story. Adv Physiol Educ 26:278–281CrossRefGoogle Scholar
  66. 66.
    Devuyst O (2012) Physiopathology and diagnosis of nephrogenic diabetes insipidus. Ann Endocrinol (Paris) 73:128–129CrossRefGoogle Scholar
  67. 67.
    Parikh CR, Coca SG (2010) Acute kidney injury: defining prerenal azotemia in clinical practice and research. Nat Rev Nephrol 6:641–642CrossRefGoogle Scholar
  68. 68.
    Fishwick C, Higgins J, Percival-Alwyn L, Hustler A, Pearson J, Bastkowski S, Moxon S, Swarbreck D, Greenman CD, Southgate J (2017) Heterarchy of transcription factors driving basal and luminal cell phenotypes in human urothelium. Cell Death Differ 24:809–818CrossRefGoogle Scholar
  69. 69.
    Rifat Y, Parekh V, Wilanowski T, Hislop NR, Auden A, Ting SB, Cunningham JM, Jane SM (2010) Regional neural tube closure defined by the grainy head-like transcription factors. Dev Biol 345:237–245CrossRefGoogle Scholar
  70. 70.
    Boglev Y, Wilanowski T, Caddy J, Parekh V, Auden A, Darido C, Hislop NR, Cangkrama M, Ting SB, Jane SM (2011) The unique and cooperative roles of the grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity. Dev Biol 349:512–522CrossRefGoogle Scholar
  71. 71.
    Moeller HB, Fenton RA (2012) Cell biology of vasopressin-regulated aquaporin-2 trafficking. Pflugers Arch 464:133–144CrossRefGoogle Scholar
  72. 72.
    Yu W, Beaudry S, Negoro H, Boucher I, Tran M, Kong T, Denker BM (2012) H2O2 activates G protein, alpha 12 to disrupt the junctional complex and enhance ischemia reperfusion injury. Proc Natl Acad Sci U S A 109:6680–6685CrossRefGoogle Scholar
  73. 73.
    Lee SY, Shin JA, Kwon HM, Weiner ID, Han KH (2011) Renal ischemia–reperfusion injury causes intercalated cell-specific disruption of occludin in the collecting duct. Histochem Cell Biol 136:637–647CrossRefGoogle Scholar
  74. 74.
    Kwon O, Nelson WJ, Sibley R, Huie P, Scandling JD, Dafoe D, Alfrey E, Myers BD (1998) Backleak, tight junctions, and cell–cell adhesion in postischemic injury to the renal allograft. J Clin Invest 101:2054–2064CrossRefGoogle Scholar
  75. 75.
    Eadon MT, Hack BK, Xu C, Ko B, Toback FG, Cunningham PN (2012) Endotoxemia alters tight junction gene and protein expression in the kidney. Am J Physiol Renal Physiol 303:F821–F830CrossRefGoogle Scholar
  76. 76.
    Grigoryev DN, Cheranova DI, Heruth DP, Huang P, Zhang LQ, Rabb H, Ye SQ (2013) Meta-analysis of molecular response of kidney to ischemia reperfusion injury for the identification of new candidate genes. BMC Nephrol 14:231CrossRefGoogle Scholar

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© IPNA 2018

Authors and Affiliations

  1. 1.Max Delbrück Center for Molecular MedicineBerlinGermany
  2. 2.Department of NephrologyCharité Medical UniversityBerlinGermany

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