Skip to main content

Advertisement

Log in

Xenopus: leaping forward in kidney organogenesis

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

While kidney donations stagnate, the number of people in need of kidney transplants continues to grow. Although transplanting culture-grown organs is years away, pursuing the engineering of the kidney de novo is a valid means of closing the gap between the supply and demand of kidneys for transplantation. The structural organization of a mouse kidney is similar to that of humans. Therefore, mice have traditionally served as the primary model system for the study of kidney development. The mouse is an ideal model organism for understanding the complexity of the human kidney. Nonetheless, the elaborate structure of the mammalian kidney makes the discovery of new therapies based on de novo engineered kidneys more challenging. In contrast to mammals, amphibians have a kidney that is anatomically less complex and develops faster. Given that analogous genetic networks regulate the development of mammalian and amphibian nephric organs, using embryonic kidneys of Xenopus laevis (African clawed frog) to analyze inductive cell signaling events and morphogenesis has many advantages. Pioneering work that led to the ability to generate kidney organoids from embryonic cells was carried out in Xenopus. In this review, we discuss how Xenopus can be utilized to compliment the work performed in mammalian systems to understand kidney development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moody SA (1987) Fates of the blastomeres of the 16-cell stage Xenopus embryo. Dev Biol 119:560–578

    Article  CAS  PubMed  Google Scholar 

  2. Moody SA (1987) Fates of the blastomeres of the 32-cell stage Xenopus embryo. Dev Biol 122:300–319

    Article  CAS  PubMed  Google Scholar 

  3. Bauer DV, Huang S, Moody SA (1994) The cleavage stage origin of Spemann’s organizer: analysis of the movements of blastomere clones before and during gastrulation in Xenopus. Development 120:1179–1189

    CAS  PubMed  Google Scholar 

  4. DeLay BD, Krneta-Stankic V, Miller RK (2016) Technique to target microinjection to the developing Xenopus kidney. J Vis Exp e53799. doi:10.3791/53799

  5. Saxén L (1987) Organogenesis of the kidney. Cambridge University Press, Cambridge

  6. Vize PD, Woolf AS, Bard JBL (2003) The kidney: from normal development to congenital disease. Academic Press, New York

  7. Romagnani P, Lasagni L, Remuzzi G (2013) Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol 9:137–146

    Article  CAS  PubMed  Google Scholar 

  8. Chan TC, Ariizumi T, Asashima M (1999) Model system for organ engineering: transplantation of in vitro induced embryonic kidney. Naturwissenschaften 86:224–227

    Article  CAS  PubMed  Google Scholar 

  9. Nieuwkoop PD, Faber J (1967) Normal table of Xenopus laevis (Daudin) : a systematical and chronological survey of the development from the fertilized egg till the end of metamorphosis. North-Holland Publ Co., Amsterdam

  10. Rak-Raszewska A, Hauser PV, Vainio S (2015) Organ in vitro culture: what have we learned about early kidney development? Stem Cells Int. 2015:959807. doi:10.1155/2015/959807

  11. Francipane MG, Lagasse E (2015) Pluripotent stem cells to rebuild a kidney: the lymph node as a possible developmental niche. Cell Transplant. doi:10.3727/096368915X688632

    PubMed  Google Scholar 

  12. Taira M, Otani H, Jamrich M, Dawid IB (1994) Expression of the LIM class homeobox gene Xlim-1 in pronephros and CNS cell lineages of Xenopus embryos is affected by retinoic acid and exogastrulation. Development 120:1525–1536

    CAS  PubMed  Google Scholar 

  13. Carroll TJ, Vize PD (1999) Synergism between Pax-8 and lim-1 in embryonic kidney development. Dev Biol 214:46–59

    Article  CAS  PubMed  Google Scholar 

  14. Haldin CE, Masse KL, Bhamra S, Simrick S, Kyuno J, Jones EA (2008) The lmx1b gene is pivotal in glomus development in Xenopus laevis. Dev Biol 322:74–85

    Article  CAS  PubMed  Google Scholar 

  15. Dudziak K, Mottalebi N, Senkel S, Edghill EL, Rosengarten S, Roose M, Bingham C, Ellard S, Ryffel GU (2008) Transcription factor HNF1beta and novel partners affect nephrogenesis. Kidney Int 74:210–217

    Article  CAS  PubMed  Google Scholar 

  16. Wild W, Pogge von Strandmann E, Nastos A, Senkel S, Lingott-Frieg A, Bulman M, Bingham C, Ellard S, Hattersley AT, Ryffel GU (2000) The mutated human gene encoding hepatocyte nuclear factor 1beta inhibits kidney formation in developing Xenopus embryos. Proc Natl Acad Sci USA 97:4695–4700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bohn S, Thomas H, Turan G, Ellard S, Bingham C, Hattersley AT, Ryffel GU (2003) Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development. J Am Soc Nephrol 14:2033–2041

    Article  CAS  PubMed  Google Scholar 

  18. Weber H, Strandmann EP, Holewa B, Bartkowski S, Zapp D, Zoidl C, Ryffel GU (1996) Regulation and function of the tissue-specific transcription factor HNF1 (LFB1) during Xenopus development. Int J Dev Biol 40:297–304

    CAS  PubMed  Google Scholar 

  19. Demartis A, Maffei M, Vignali R, Barsacchi G, De Simone V (1994) Cloning and developmental expression of LFB3/HNF1 beta transcription factor in Xenopus laevis. Mech Dev 47:19–28

    Article  CAS  PubMed  Google Scholar 

  20. Bartkowski S, Zapp D, Weber H, Eberie G, Zoidi C, Senkel S, Klein-Hitpass L, Ryfell GU (1993) Developmental regulation and tissue distribution of the liver transcription factor LFB1 (HNF1) in Xenopus laevis. Mol Cell Biol 13:421–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Buisson I, Le Bouffant R, Futel M, Riou JF, Umbhauer M (2015) Pax8 and Pax2 are specifically required at different steps of Xenopus pronephros development. Dev Biol 397:175–190

    Article  CAS  PubMed  Google Scholar 

  22. Heller N, Brändli AW (1999) Xenopus Pax-2/5/8 orthologues: novel insights into pax gene evolution and identification of pax-8 as the earliest marker for otic and pronephric cell lineages. Dev Genet 24:208–219

    Article  CAS  PubMed  Google Scholar 

  23. Heller N, Brändli AW (1997) Xenopus pax-2 displays multiple splice forms during embryogenesis and pronephric kidney development. Mech Dev 69:83–104

    Article  CAS  PubMed  Google Scholar 

  24. Taelman V, Van Campenhout C, Sölter M, Pieler T, Bellefroid EJ (2006) The Notch-effector HRT1 gene plays a role in glomerular development and patterning of the Xenopus pronephros anlagen. Development 133:2961–2971

    Article  CAS  PubMed  Google Scholar 

  25. Carroll TJ, Wallingford JB, Vize PD (1999) Dynamic patterns of gene expression in the developing pronephros of Xenopus laevis. Dev Genet 24:199–207

    Article  CAS  PubMed  Google Scholar 

  26. Carroll TJ, Vize PD (1996) Wilms tumor suppressor gene is involved in the development of disparate kidney forms: evidence from expression in the Xenopus pronephros. Dev Dyn 206:131–138

    Article  CAS  PubMed  Google Scholar 

  27. Murugan S, Shan J, Kühl SJ, Tata A, Pietilä I, Kühl M, Vainio SJ (2012) WT1 and Sox11 regulate synergistically the promoter of the Wnt4 gene that encodes a critical signal for nephrogenesis. Exp Cell Res 318:1134–1145

    Article  CAS  PubMed  Google Scholar 

  28. Kyuno J, Jones EA (2007) GDNF expression during Xenopus development. Gene Expr Patterns 7:313–317

    Article  CAS  PubMed  Google Scholar 

  29. Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P, Smith D, Ponder B, Costantini F, Saarma M, Sariola H, Pachnis V (1996) GDNF signalling through the Ret receptor tyrosine kinase. Nature 381:789–793

    Article  CAS  PubMed  Google Scholar 

  30. Hawley SH, Wünnenberg-Stapleton K, Hashimoto C, Laurent MN, Watabe T, Blumberg BW, Cho KW (1995) Disruption of BMP signals in embryonic Xenopus ectoderm leads to direct neural induction. Genes Dev 9:2923–2935

    Article  CAS  PubMed  Google Scholar 

  31. Alarcón P, Rodríguez-Seguel E, Fernández-González A, Rubio R, Gómez-Skarmeta JL (2008) A dual requirement for Iroquois genes during Xenopus kidney development. Development 135:3197–3207

    Article  PubMed  Google Scholar 

  32. Wang S, Krinks M, Kleinwaks L, Moos M (1997) A novel Xenopus homologue of bone morphogenetic protein-7 (BMP-7). Genes Funct 1:259–271

    Article  CAS  PubMed  Google Scholar 

  33. Saulnier DME, Ghanbari H, Brändli AW (2002) Essential function of Wnt-4 for Tubulogenesis in the Xenopus pronephric kidney. Dev Biol 248:13–28

    Article  CAS  PubMed  Google Scholar 

  34. Tena JJ, Neto A, de la Calle-Mustienes E, Bras-Pereira C, Casares F, Gómez-Skarmeta JL (2007) Odd-skipped genes encode repressors that control kidney development. Dev Biol 301:518–531

    Article  CAS  PubMed  Google Scholar 

  35. Zhou X, Vize PD (2004) Proximo-distal specialization of epithelial transport processes within the Xenopus pronephric kidney tubules. Dev Biol 271:322–338

    Article  CAS  PubMed  Google Scholar 

  36. Raciti D, Reggiani L, Geffers L, Jiang Q, Bacchion F, Subrizi AE, Clements D, Tindal C, Davidson DR, Kaissling B, Brandli AW (2008) Organization of the pronephric kidney revealed by large-scale gene expression mapping. Genome Biol 9:R84

    Article  PubMed  PubMed Central  Google Scholar 

  37. Brändli AW (1999) Towards a molecular anatomy of the Xenopus pronephric kidney. Int J Dev Biol 43:381–395

    PubMed  Google Scholar 

  38. Jones EA (2005) Xenopus: a prince among models for pronephric kidney development. J Am Soc Nephrol 16:313–321

    Article  CAS  PubMed  Google Scholar 

  39. Wessely O, Tran U (2011) Xenopus pronephros development—past, present, and future. Pediatr Nephrol 26:1545–1551

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wingert RA, Davidson AJ (2008) The zebrafish pronephros: a model to study nephron segmentation. Kidney Int 73:1120–1127

    Article  CAS  PubMed  Google Scholar 

  41. Vize PD, Seufert DW, Carroll TJ, Wallingford JB (1997) Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning. Dev Biol 188:189–204

    Article  CAS  PubMed  Google Scholar 

  42. Miller RK, Lee M, McCrea PD (2014) Chapter 12: The Xenopus Pronephros: A Kidney Model Making Leaps toward Understanding Tubule Development. In: Kloc M, Kubiak JZ (eds) Xenopus Development. Oxford: John Wiley & Sons. pp. 215–238. doi:10.1002/9781118492833.ch12

  43. Vize PD, Jones EA, Pfister R (1995) Development of the Xenopus pronephric system. Dev Biol 171:531–540

    Article  CAS  PubMed  Google Scholar 

  44. Brennan HC, Nijjar S, Jones EA (1999) Glomus specification and induction in Xenopus. Development 126:5847–5856

  45. Brennan HC, Nijjar S, Jones EA (1998) The specification of the pronephric tubules and duct in Xenopus laevis. Mech Dev 75:127–137

    Article  CAS  PubMed  Google Scholar 

  46. Moriya N, Uchiyama H, Asashima M (1993) Induction of pronephric tubules by activin and retinoic acid in presumptive ectoderm of Xenopus laevis. Dev Growth Differ 35:123–128

    Article  CAS  Google Scholar 

  47. Drews C, Senkel S, Ryffel GU (2011) The nephrogenic potential of the transcription factors osr1, osr2, hnf1b, lhx1 and pax8 assessed in Xenopus animal caps. BMC Dev Biol 11:5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Osafune K, Nishinakamura R, Komazaki S, Asashima M (2002) In vitro induction of the pronephric duct in Xenopus explants. Dev Growth Differ 44:161–167

    Article  PubMed  Google Scholar 

  49. Uochi T, Asashima M (1996) Sequential gene expression during pronephric tubule formation in vitro in Xenopus ectoderm. Dev Growth Differ 38:625–634

    Article  CAS  Google Scholar 

  50. Moon KH, Ko IK, Yoo JJ, Atala A (2015) Kidney diseases and tissue engineering. Methods. doi:10.1016/j.ymeth.2015.06.020

    PubMed  Google Scholar 

  51. Rak-Raszewska A, Hauser VP, Vainio S (2015) Organ in vitro culture: what have we learned about early kidney development? Stem Cells. 2015:959807. doi:10.1155/2015/959807

  52. Ekblom P, Miettinen A, Virtanen I, Wahlström T, Dawnay A, Saxén L (1981) In vitro segregation of the metanephric nephron. Dev Biol 84:88–95

    Article  CAS  PubMed  Google Scholar 

  53. Thesleff I, Ekblom P (1984) Role of transferrin in branching morphogenesis, growth and differentiation of the embryonic kidney. J Embryol Exp Morph 82:147–161

    CAS  PubMed  Google Scholar 

  54. Kyuno J, Massé K, Jones EA (2008) A functional screen for genes involved in Xenopus pronephros development. Mech Dev 125:571–586

    Article  CAS  PubMed  Google Scholar 

  55. Tomlinson ML, Hendry AE, Wheeler GN (2012) Xenopus protocols. Methods in molecular biology. Humana Press, Clifton

  56. Schmitt SM, Gull M, Brändli AW (2014) Engineering Xenopus embryos for phenotypic drug discovery screening. Adv Drug Deliv Rev 69–70:225–246

    Article  PubMed  Google Scholar 

  57. Kim D, Dressler GR (2005) Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol 16:3527–3534

    Article  CAS  PubMed  Google Scholar 

  58. Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH (2015) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:564–568

    Article  CAS  PubMed  Google Scholar 

  59. Keller R, Danilchik M, Gimlich R, Shih J (1985) The function and mechanism of convergent extension during gastrulation of Xenopus laevis. J Embryol Exp Morpholog 89[Suppl]:185–209

    Google Scholar 

  60. Keller R, Davidson LA, Shook DR (2003) How we are shaped: the biomechanics of gastrulation. Differentiation 71:171–205

    Article  PubMed  Google Scholar 

  61. Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, Carroll TJ (2009) Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 41:793–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. McCoy KE, Zhou X, Vize PD (2011) Non-canonical wnt signals antagonize and canonical wnt signals promote cell proliferation in early kidney development. Dev Dyn 240(6):1558–66. doi:10.1002/dvdy.22626.63

  63. Miller RK, Canny SG, Jang CW, Cho K, Ji H, Wagner DS, Jones EA, Habas R, McCrea PD (2011) Pronephric tubulogenesis requires Daam1-mediated planar cell polarity signaling. J Am Soc Nephrol 22(9):1654–64. doi:10.1681/ASN.2010101086

  64. Lienkamp SS, Liu K, Karner CM, Carroll TJ, Ronneberger O, Wallingford JB, Walz G (2012) Vertebrate kidney tubules elongate using a planar cell polarity-dependent, rosette-based mechanism of convergent extension. Nat Genet 44:1382–1387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Blankenship JT, Backovic ST, Sanny JSP, Weitz O, Zallen JA (2006) Multicellular rosette formation links planar cell polarity to tissue morphogenesis. Dev Cell 11:459–470

    Article  CAS  PubMed  Google Scholar 

  66. Lienkamp S, Ganner A, Boehlke C, Schmidt T, Arnold SJ, Schäfer T, Romaker D, Schuler J, Hoff S, Powelske C, Eifler A, Krönig C, Bullerkotte A, Nitschke R, Kuehn EW, Kim E, Burkhardt H, Brox T, Ronneberger O, Gloy J, Walz G (2010) Inversin relays Frizzled-8 signals to promote proximal pronephros development. Proc Natl Acad Sci USA 47:20388–20393

    Article  Google Scholar 

  67. Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kronig C, Schermer B, Benzing T, Cabella OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37(5):537–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Srinivas S, Goldberg MR, Watanabe T, D’Agati V, Al-Awqati Q, Costantini F (1999) Expression of green fluorescent protein in the ureteric bud of transgenic mice: a new tool for the analysis of ureteric bud morphogenesis. Dev Genet 24:241–251

    Article  CAS  PubMed  Google Scholar 

  69. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht J, Asai N, Takahashi M, Ohgami N, Kato M, Mendelsohn C, Costantini F (2009) Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell 17(2):199–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Packard A, Georgas K, Michos O, Riccio P, Cebrian C, Combes A, Ju A, Ferrer-Vaquer A, Hadjantonakis AK, Zong H, Little MH, Costantini F (2013) Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud. Dev Cell 27(3):319–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pan X, Schnell U, Karner CM, Small EV, Carroll TJ (2015) A Cre-inducible fluorescent reporter for observing apical membrane dynamics. Genesis 53:285–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Blitz IL, Biesinger J, Xie X, Cho KWY (2013) Biallelic genome modification in F0 Xenopus tropicalis embryos using the CRISPR/Cas system. Genesis 51:827–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nakayama T, Fish MB, Fisher M, Oomen-Hajagos J, Thomsen GH, Grainger RM (2013) Simple and efficient CRISPR/Cas9-mediated targeted mutagenesis in Xenopus tropicalis. Genesis 51:835–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang F, Shi Z, Cui Y, Guo X, Shi Y-B, Chen Y (2015) Targeted gene disruption in Xenopus laevis using CRISP/Cas9. Cell Biosci 5:15. doi:10.1186/s13578-015-0006-1

    Article  PubMed  PubMed Central  Google Scholar 

  75. Caine ST, Mclaughlin KA (2013) Regeneration of functional pronephric proximal tubules after partial nephrectomy in Xenopus laevis. Dev Dyn 242:219–229

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Lance Davidson, Mark Corkins and Soeren Lienkamp for critical reading of the manuscript and thoughtful suggestions. This work was funded by a National Institutes of Health NIDDK grant (K01DK092320) and startup funding from the Department of Pediatrics at the University of Texas McGovern Medical School.

Conflict of interest statement

The authors declare that they have no conflicts of interest

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rachel K. Miller.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Krneta-Stankic, V., DeLay, B.D. & Miller, R.K. Xenopus: leaping forward in kidney organogenesis. Pediatr Nephrol 32, 547–555 (2017). https://doi.org/10.1007/s00467-016-3372-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-016-3372-y

Keywords

Navigation