Abstract
Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans.
Similar content being viewed by others
References
Bates CM (2011) Role of fibroblast growth factor receptor signaling in kidney development. Pediatr Nephrol 26:1373–1379
Qiao J, Uzzo R, Obara-Ishihara T, Degenstein L, Fuchs E, Herzlinger D (1999) FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126:547–554
Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N (2000) FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277:643–649
Revest JM, Spencer-Dene B, Kerr K, De Moerlooze L, Rosewell I, Dickson C (2001) Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Dev Biol 231:47–62
Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, Baum M, Bates CM (2004) Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol 276:403–415
Sims-Lucas S, Argyropoulos C, Kish K, McHugh K, Bertram JF, Quigley R, Bates CM (2009) Three-dimensional imaging reveals ureteric and mesenchymal defects in Fgfr2-mutant kidneys. J Am Soc Nephrol 20:2525–2533
Sims-Lucas S, Cullen-McEwen L, Eswarakumar VP, Hains D, Kish K, Becknell B, Zhang J, Bertram JF, Wang F, Bates CM (2009) Deletion of Frs2alpha from the ureteric epithelium causes renal hypoplasia. Am J Physiol Ren Physiol 297:F1208–1219
Sims-Lucas S, Cusack B, Eswarakumar VP, Zhang J, Wang F, Bates CM (2011) Independent roles of Fgfr2 and Frs2{alpha} in ureteric epithelium. Development 138:1275–1280
Okazawa M, Murashima A, Harada M, Nakagata N, Noguchi M, Morimoto M, Kimura T, Ornitz DM, Yamada G (2015) Region-specific regulation of cell proliferation by FGF receptor signaling during the Wolffian duct development. Dev Biol 400:139–147
Grieshammer U, Cebrian C, Ilagan R, Meyers E, Herzlinger D, Martin GR (2005) FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons. Development 132:3847–3857
Perantoni AO, Timofeeva O, Naillat F, Richman C, Pajni-Underwood S, Wilson C, Vainio S, Dove LF, Lewandoski M (2005) Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development 132:3859–3871
Gerber SD, Steinberg F, Beyeler M, Villiger PM, Trueb B (2009) The murine Fgfrl1 receptor is essential for the development of the metanephric kidney. Dev Biol 335:106–119
Poladia DP, Kish K, Kutay B, Hains D, Kegg H, Zhao H, Bates CM (2006) Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol 291:325–339
Sims-Lucas S, Cusack B, Baust J, Eswarakumar VP, Masatoshi H, Takeuchi A, Bates CM (2011) Fgfr1 and the IIIc isoform of Fgfr2 play critical roles in the metanephric mesenchyme mediating early inductive events in kidney development. Dev Dyn 240:240–249
Sims-Lucas S, Di Giovanni V, Schaefer C, Cusack B, Eswarakumar VP, Bates CM (2012) Ureteric morphogenesis requires Fgfr1 and Fgfr2/Frs2alpha signaling in the metanephric mesenchyme. J Am Soc Nephrol 23:607–617
Di Giovanni V, Walker KA, Bushnell D, Schaefer C, Sims-Lucas S, Puri P, Bates CM (2015) Fibroblast growth factor receptor-Frs2alpha signaling is critical for nephron progenitors. Dev Biol 400:82–93
Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, Bole-Feysot C, Nitschke P, Salomon R, Antignac C, Ornitz DM, Kopan R (2012) FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell 22:1191–1207
Hains D, Sims-Lucas S, Kish K, Saha M, McHugh K, Bates CM (2008) Role of fibroblast growth factor receptor 2 in kidney mesenchyme. Pediatr Res 64:592–598
Hains DS, Sims-Lucas S, Carpenter A, Saha M, Murawski I, Kish K, Gupta I, McHugh K, Bates CM (2010) High incidence of vesicoureteral reflux in mice with Fgfr2 deletion in kidney mesenchyma. J Urol 183:2077–2084
Walker KA, Sims-Lucas S, Di Giovanni VE, Schaefer C, Sunseri WM, Novitskaya T, de Caestecker MP, Chen F, Bates CM (2013) Deletion of fibroblast growth factor receptor 2 from the peri-Wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux. PLoS One 8:e56062
Walker KA, Ikeda Y, Zabbarova I, Schaefer CM, Bushnell D, De Groat WC, Kanai A, Bates CM (2015) Fgfr2 is integral for bladder mesenchyme patterning and function. Am J Physiol Ren Physiol 308:F888–898
Bates CM (2011) Role of fibroblast growth factor receptor signaling in kidney development. Am J Physiol Ren Physiol 301:F245–251
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129
Peters KG, Werner S, Chen G, Williams LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114:233–243
Dudley AT, Godin RE, Robertson EJ (1999) Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme. Genes Dev 13:1601–1613
Cancilla B, Ford-Perriss MD, Bertram JF (1999) Expression and localization of fibroblast growth factors and fibroblast growth factor receptors in the developing rat kidney. Kidney Int 56:2025–2039
Fuhrmann V, Kinkl N, Leveillard T, Sahel J, Hicks D (1999) Fibroblast growth factor receptor 4 (FGFR4) is expressed in adult rat and human retinal photoreceptors and neurons. J Mol Neurosci 13:187–197
Celli G, LaRochelle WJ, Mackem S, Sharp R, Merlino G (1998) Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning. EMBO J 17:1642–1655
Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12:390–397
Weinstein M, Xu X, Ohyama K, Deng CX (1998) FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development 125:3615–3623
Yamaguchi TP, Harpal K, Henkemeyer M, Rossant J (1994) Fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev 8:3032–3044
Deng CX, Wynshaw-Boris A, Shen MM, Daugherty C, Ornitz DM, Leder P (1994) Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev 8:3045–3057
Xu X, Weinstein M, Li C, Naski M, Cohen RI, Ornitz DM, Leder P, Deng C (1998) Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125:753–765
Arman E, Haffner-Krausz R, Chen Y, Heath JK, Lonai P (1998) Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc Natl Acad Sci U S A 95:5082–5087
Krause M, Rak-Raszewska A, Pietila I, Quaggin SE, Vainio S (2015) Signaling during kidney development. Cell 4:112–132
Airik R, Bussen M, Singh MK, Petry M, Kispert A (2006) Tbx18 regulates the development of the ureteral mesenchyme. J Clin Invest 116:663–67
Sims-Lucas S, Schaefer C, Bushnell D, Ho J, Logar A, Prochownik E, Gittes G, Bates CM (2013) Endothelial progenitors exist within the kidney and lung mesenchyme. PLoS One 8:e65993
Rasouly HM, Lu W (2013) Lower urinary tract development and disease. Wiley Interdiscip Rev Syst Biol Med 5:307–342
Brenner-Anantharam A, Cebrian C, Guillaume R, Hurtado R, Sun TT, Herzlinger D (2007) Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling. Development 134:1967–1975
Qiao J, Bush KT, Steer DL, Stuart RO, Sakurai H, Wachsman W, Nigam SK (2001) Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis. Mech Dev 109:123–135
Nguyen HQ, Danilenko DM, Bucay N, DeRose ML, Van GY, Thomason A, Simonet WS (1996) Expression of keratinocyte growth factor in embryonic liver of transgenic mice causes changes in epithelial growth and differentiation resulting in polycystic kidneys and other organ malformations. Oncogene 12:2109–2119
Li Z, Jerebtsova M, Liu XH, Tang P, Ray PE (2006) Novel cystogenic role of basic fibroblast growth factor in developing rodent kidneys. Am J Physiol Ren Physiol 291:F289–296
Michos O, Cebrian C, Hyink D, Grieshammer U, Williams L, D’Agati V, Licht JD, Martin GR, Costantini F (2010) Kidney development in the absence of gdnf and Spry1 requires Fgf10. PLoS Genet 6:e1000809
Pitera JE, Woolf AS, Basson MA, Scambler PJ (2012) Sprouty1 haploinsufficiency prevents renal agenesis in a model of Fraser syndrome. J Am Soc Nephrol 23:1790–1796
Schuchardt A, D’Agati V, Pachnis V, Costantini F (1996) Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development 122:1919–1929
Poladia DP, Kish K, Kutay B, Bauer J, Baum M, Bates CM (2006) Link between reduced nephron number and hypertension: studies in a mutant mouse model. Pediatr Res 59:489–493
Perantoni AO, Dove LF, Karavanova I (1995) Basic fibroblast growth factor can mediate the early inductive events in renal development. Proc Natl Acad Sci U S A 92:4696–4700
Barasch J, Qiao J, McWilliams G, Chen D, Oliver JA, Herzlinger D (1997) Ureteric bud cells secrete multiple factors, including bFGF, which rescue renal progenitors from apoptosis. Am J Physiol 273:F757–767
Barasch J, Yang J, Ware CB, Taga T, Yoshida K, Erdjument-Bromage H, Tempst P, Parravicini E, Malach S, Aranoff T, Oliver JA (1999) Mesenchymal to epithelial conversion in rat metanephros is induced by LIF. Cell 99:377–386
Plisov SY, Yoshino K, Dove LF, Higinbotham KG, Rubin JS, Perantoni AO (2001) TGF beta 2, LIF and FGF2 cooperate to induce nephrogenesis. Development 128:1045–1057
Brennan HC, Nijjar S, Jones EA (1999) The specification and growth factor inducibility of the pronephric Glomus in Xenopus laevis. Development 126:5847–5856
Zhou M, Sutliff RL, Paul RJ, Lorenz JN, Hoying JB, Haudenschild CC, Yin M, Coffin JD, Kong L, Kranias EG, Luo W, Boivin GP, Duffy JJ, Pawlowski SA, Doetschman T (1998) Fibroblast growth factor 2 control of vascular tone. Nat Med 4:201–207
Brown AC, Adams D, de Caestecker M, Yang X, Friesel R, Oxburgh L (2011) FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development. Development 138:5099–5112
Miller DL, Ortega S, Bashayan O, Basch R, Basilico C (2000) Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 20:2260–2268
Motamedi FJ, Badro DA, Clarkson M, Lecca MR, Bradford ST, Buske FA, Saar K, Hubner N, Brandli AW, Schedl A (2014) WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors. Nat Commun 5:4444
Ahn SY, Kim Y, Kim ST, Swat W, Miner JH (2013) Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development. J Am Soc Nephrol 24:1127–1138
Cain JE, Bertram JF (2006) Ureteric branching morphogenesis in BMP4 heterozygous mutant mice. J Anat 209:745–755
Miyazaki Y, Oshima K, Fogo A, Hogan BL, Ichikawa I (2000) Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J Clin Invest 105:863–873
Passos-Bueno MR, Wilcox WR, Jabs EW, Sertie AL, Alonso LG, Kitoh H (1999) Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat 14:115–125
Cohen MM Jr, Kreiborg S (1993) Visceral anomalies in the Apert syndrome. Am J Med Genet 45:758–760
Sergi C, Stein H, Heep JG, Otto HF (1997) A 19-week-old fetus with craniosynostosis, renal agenesis and gastroschisis: case report and differential diagnosis. Pathol Res Pract 193:579–585, discussion 587–578
Seyedzadeh A, Kompani F, Esmailie E, Samadzadeh S, Farshchi B (2008) High-grade vesicoureteral reflux in Pfeiffer syndrome. Urol J 5:200–202
Dode C, Hardelin JP (2010) Clinical genetics of Kallmann syndrome. Ann Endocrinol (Paris) 71:149–157
Tohya T, Miura K, Nagata N (1986) A case of thanatophoric dwarfism with renal hypoplasia. Pediatr Int 28:232–237
Prontera P, Sensi A, Pilu G, Baldi M, Baffico M, Bonasoni R, Calzolari E (2006) FGFR3 mutation in thanatophoric dysplasia type 1 with bilateral cystic renal dysplasia: coincidence or a new association? Genet Couns 17:407–412
Sanna-Cherchi S, Sampogna RV, Papeta N, Burgess KE, Nees SN, Perry BJ, Choi M, Bodria M, Liu Y, Weng PL, Lozanovski VJ, Verbitsky M, Lugani F, Sterken R, Paragas N, Caridi G, Carrea A, Dagnino M, Materna-Kiryluk A, Santamaria G, Murtas C, Ristoska-Bojkovska N, Izzi C, Kacak N, Bianco B, Giberti S, Gigante M, Piaggio G, Gesualdo L, Kosuljandic Vukic D, Vukojevic K, Saraga-Babic M, Saraga M, Gucev Z, Allegri L, Latos-Bielenska A, Casu D, State M, Scolari F, Ravazzolo R, Kiryluk K, Al-Awqati Q, D’Agati VD, Drummond IA, Tasic V, Lifton RP, Ghiggeri GM, Gharavi AG (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621–629
Yamzon J, Hwa Lee K, Kuremoto K, Parsa S, Bellusci S, Warburton D, Kho C (2011) FGF10/FGFR2B signaling during acute cyclophosphamide-induced bladder urothelial injury in mice. J Urol 165:e547–548
Ulich TR, Whitcomb L, Tang W, O’Conner Tressel P, Tarpley J, Yi ES, Lacey D (1997) Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis. Cancer Res 57:472–475
Acknowledgments
The authors wish to thank Elsevier, the American Society of Nephrology, and the American Physiological Society for permission to reprint some of the figures used in the publication. Some of the work presented was supported by grants from the National Institutes of Health, including R01 DK 070030, R01 DK 081128, and R01 DK095748 (C.M.B.).
Conflict of interest
The authors declare that they have no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Walker, K.A., Sims-Lucas, S. & Bates, C.M. Fibroblast growth factor receptor signaling in kidney and lower urinary tract development. Pediatr Nephrol 31, 885–895 (2016). https://doi.org/10.1007/s00467-015-3151-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-015-3151-1