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.
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References
Moody SA (1987) Fates of the blastomeres of the 16-cell stage Xenopus embryo. Dev Biol 119:560–578
Moody SA (1987) Fates of the blastomeres of the 32-cell stage Xenopus embryo. Dev Biol 122:300–319
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
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
Saxén L (1987) Organogenesis of the kidney. Cambridge University Press, Cambridge
Vize PD, Woolf AS, Bard JBL (2003) The kidney: from normal development to congenital disease. Academic Press, New York
Romagnani P, Lasagni L, Remuzzi G (2013) Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol 9:137–146
Chan TC, Ariizumi T, Asashima M (1999) Model system for organ engineering: transplantation of in vitro induced embryonic kidney. Naturwissenschaften 86:224–227
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
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
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
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
Carroll TJ, Vize PD (1999) Synergism between Pax-8 and lim-1 in embryonic kidney development. Dev Biol 214:46–59
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
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
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
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
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
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
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
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
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
Heller N, Brändli AW (1997) Xenopus pax-2 displays multiple splice forms during embryogenesis and pronephric kidney development. Mech Dev 69:83–104
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
Carroll TJ, Wallingford JB, Vize PD (1999) Dynamic patterns of gene expression in the developing pronephros of Xenopus laevis. Dev Genet 24:199–207
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
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
Kyuno J, Jones EA (2007) GDNF expression during Xenopus development. Gene Expr Patterns 7:313–317
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
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
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
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
Saulnier DME, Ghanbari H, Brändli AW (2002) Essential function of Wnt-4 for Tubulogenesis in the Xenopus pronephric kidney. Dev Biol 248:13–28
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
Zhou X, Vize PD (2004) Proximo-distal specialization of epithelial transport processes within the Xenopus pronephric kidney tubules. Dev Biol 271:322–338
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
Brändli AW (1999) Towards a molecular anatomy of the Xenopus pronephric kidney. Int J Dev Biol 43:381–395
Jones EA (2005) Xenopus: a prince among models for pronephric kidney development. J Am Soc Nephrol 16:313–321
Wessely O, Tran U (2011) Xenopus pronephros development—past, present, and future. Pediatr Nephrol 26:1545–1551
Wingert RA, Davidson AJ (2008) The zebrafish pronephros: a model to study nephron segmentation. Kidney Int 73:1120–1127
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
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
Vize PD, Jones EA, Pfister R (1995) Development of the Xenopus pronephric system. Dev Biol 171:531–540
Brennan HC, Nijjar S, Jones EA (1999) Glomus specification and induction in Xenopus. Development 126:5847–5856
Brennan HC, Nijjar S, Jones EA (1998) The specification of the pronephric tubules and duct in Xenopus laevis. Mech Dev 75:127–137
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
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
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
Uochi T, Asashima M (1996) Sequential gene expression during pronephric tubule formation in vitro in Xenopus ectoderm. Dev Growth Differ 38:625–634
Moon KH, Ko IK, Yoo JJ, Atala A (2015) Kidney diseases and tissue engineering. Methods. doi:10.1016/j.ymeth.2015.06.020
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
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
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
Kyuno J, Massé K, Jones EA (2008) A functional screen for genes involved in Xenopus pronephros development. Mech Dev 125:571–586
Tomlinson ML, Hendry AE, Wheeler GN (2012) Xenopus protocols. Methods in molecular biology. Humana Press, Clifton
Schmitt SM, Gull M, Brändli AW (2014) Engineering Xenopus embryos for phenotypic drug discovery screening. Adv Drug Deliv Rev 69–70:225–246
Kim D, Dressler GR (2005) Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol 16:3527–3534
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
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
Keller R, Davidson LA, Shook DR (2003) How we are shaped: the biomechanics of gastrulation. Differentiation 71:171–205
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Caine ST, Mclaughlin KA (2013) Regeneration of functional pronephric proximal tubules after partial nephrectomy in Xenopus laevis. Dev Dyn 242:219–229
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.
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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
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DOI: https://doi.org/10.1007/s00467-016-3372-y