Seminars in Nephrology
Volume 29, Issue 4 , Pages 321-337 , July 2009

Cell and Molecular Biology of Kidney Development

  • Kimberly J. Reidy, MD

      Affiliations

    • Department of Pediatrics/Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
    • Corresponding Author InformationAddress reprint requests to Kimberly J. Reidy, MD, Department of Pediatrics/Division of Pediatric Nephrology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, 3415 Bainbridge Ave, Bronx, NY 10467
  • ,
  • Norman D. Rosenblum, MD

      Affiliations

    • Department of Pediatrics, Physiology and Laboratory Medicine and Pathobiology, University of Toronto, Program in Developmental and Stem Cell Biology, Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada

References 

  1. Saxen L, Sariola H. Early organogenesis of the kidney. Pediatr Nephrol. 1987;1:385–392
  2. Holliday MA, Barratt TM, Avner ED. Pediatric nephrology. In: 3rd ed.. Baltimore: Williams & Wilkins; 1994;p. 3–24p. i
  3. Sariola H. Interspecies chimeras: an experimental approach for studies on embryonic angiogenesis. Med Biol. 1985;63:43–65
  4. Eremina V, Baelde HJ, Quaggin SE. Role of the VEGF—a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol. 2007;106:32–37
  5. Pichel JG, Shen L, Sheng HZ, et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996;382:73–76
  6. Fazan VP, Ma X, Chapleau MW, Barreira AA. Qualitative and quantitative morphology of renal nerves in C57BL/6J mice. Anat Rec. 2002;268:399–404
  7. Park JS, Valerius MT, McMahon AP. Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development. Development. 2007;134:2533–2539
  8. Bridgewater D, Cox B, Cain J, et al. Canonical WNT/beta-catenin signaling is required for ureteric branching. Dev Biol. 2008;317:83–94
  9. Rothenpieler UW, Dressler GR. Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development. 1993;119:711–720
  10. Narlis M, Grote D, Gaitan Y, Boualia SK, Bouchard M. Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol. 2007;18:1121–1129
  11. Iglesias DM, Hueber PA, Chu L, et al. Canonical WNT signaling during kidney development. Am J Physiol Renal Physiol. 2007;293:F494–F500
  12. James RG, Kamei CN, Wang Q, Jiang R, Schultheiss TM. Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells. Development. 2006;133:2995–3004
  13. Stricker S, Brieske N, Haupt J, Mundlos S. Comparative expression pattern of Odd-skipped related genes Osr1 and Osr2 in chick embryonic development. Gene Expr Patterns. 2006;6:826–834
  14. Mugford JW, Sipila P, McMahon JA, McMahon AP. Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Dev Biol. 2008;324:88–98
  15. Drummond IA. The zebrafish pronephros: a genetic system for studies of kidney development. Pediatr Nephrol. 2000;14:428–435
  16. Tena JJ, Neto A, de la Calle-Mustienes E, et al. Odd-skipped genes encode repressors that control kidney development. Dev Biol. 2007;301:518–531
  17. Mudumana SP, Hentschel D, Liu Y, Vasilyev A, Drummond IA. Odd skipped related1 reveals a novel role for endoderm in regulating kidney versus vascular cell fate. Development. 2008;135:3355–3367
  18. Vize PD, Seufert DW, Carroll TJ, Wallingford JB. Model systems for the study of kidney development: use of the pronephros in the analysis of organ induction and patterning. Dev Biol. 1997;188:189–204
  19. Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247–254
  20. Xu PX, Zheng W, Huang L, et al. Six1 is required for the early organogenesis of mammalian kidney. Development. 2003;130:3085–3094
  21. Gong KQ, Yallowitz AR, Sun H, Dressler GR, Wellik DM. A Hox-Eya-Pax complex regulates early kidney developmental gene expression. Mol Cell Biol. 2007;27:7661–7668
  22. Ruf RG, Xu PX, Silvius D, et al. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004;101:8090–8095
  23. Kobayashi H, Kawakami K, Asashima M, Nishinakamura R. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech Dev. 2007;124:290–303
  24. Chai L, Yang J, Di C, et al. Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development. J Biol Chem. 2006;281:18918–18926
  25. Nishinakamura R, Matsumoto Y, Nakao K, et al. Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development. 2001;128:3105–3115
  26. Self M, Lagutin OV, Bowling B, et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J. 2006;25:5214–5228
  27. Kobayashi A, Valerius MT, Mugford JW, et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell. 2008;3:169–181
  28. Kobayashi A, Kwan KM, Carroll TJ, et al. Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development. 2005;132:2809–2823
  29. Potter SS, Hartman HA, Kwan KM, Behringer RR, Patterson LT. Laser capture-microarray analysis of Lim1 mutant kidney development. Genesis. 2007;45:432–439
  30. Kreidberg JA, Sariola H, Loring JM, et al. WT-1 is required for early kidney development. Cell. 1993;74:679–691
  31. Dehbi M, Pelletier J. PAX8-mediated activation of the wt1 tumor suppressor gene. EMBO J. 1996;15:4297–4306
  32. Gao X, Chen X, Taglienti M, et al. Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa. Development. 2005;132:5437–5449
  33. Donovan MJ, Natoli TA, Sainio K, et al. Initial differentiation of the metanephric mesenchyme is independent of WT1 and the ureteric bud. Dev Genet. 1999;24:252–262
  34. Weber S, Moriniere V, Knuppel T, et al. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol. 2006;17:2864–2870
  35. Sakaki-Yumoto M, Kobayashi C, Sato A, et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development. 2006;133:3005–3013
  36. Levinson RS, Batourina E, Choi C, et al. Foxd1-dependent signals control cellularity in the renal capsule, a structure required for normal renal development. Development. 2005;132:529–539
  37. Tufro A, Norwood VF, Carey RM, Gomez RA. Vascular endothelial growth factor induces nephrogenesis and vasculogenesis. J Am Soc Nephrol. 1999;10:2125–2134
  38. Tufro A. VEGF spatially directs angiogenesis during metanephric development in vitro. Dev Biol. 2000;227:558–566
  39. Schmidt-Ott KM, Chen X, Paragas N, et al. c-kit delineates a distinct domain of progenitors in the developing kidney. Dev Biol. 2006;299:238–249
  40. Wellik DM, Hawkes PJ, Capecchi MR. Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev. 2002;16:1423–1432
  41. Mugford JW, Sipila P, Kobayashi A, Behringer RR, McMahon AP. Hoxd11 specifies a program of metanephric kidney development within the intermediate mesoderm of the mouse embryo. Dev Biol. 2008;319:396–405
  42. Watanabe T, Costantini F. Real-time analysis of ureteric bud branching morphogenesis in vitro. Dev Biol. 2004;271:98–108
  43. Bridgewater D, Cox B, Cain J, et al. Canonical WNT/beta-catenin signaling is required for ureteric branching. Dev Biol. 2008;317:83–94
  44. Moore MW, Klein RD, Farinas I, et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature. 1996;382:76–79
  45. Pichel JG, Shen L, Sheng HZ, et al. GDNF is required for kidney development and enteric innervation. Cold Spring Harb Symp Quant Biol. 1996;61:445–457
  46. Sanchez MP, Silos-Santiago I, Frisen J, et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature. 1996;382:70–73
  47. Vega QC, Worby CA, Lechner MS, Dixon JE, Dressler GR. Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc Natl Acad Sci U S A. 1996;93:10657–10661
  48. Durbec P, Marcos-Gutierrez CV, Kilkenny C, et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature. 1996;381:789–793
  49. Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994;367:380–383
  50. Moreau E, Vilar J, Lelievre-Pegorier M, Merlet-Benichou C, Gilbert T. Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control. Am J Physiol. 1998;275:F938–F945
  51. Tang MJ, Cai Y, Tsai SJ, et al. Ureteric bud outgrowth in response to RET activation is mediated by phosphatidylinositol 3-kinase. Dev Biol. 2002;243:128–136
  52. Kim D, Dressler GR. PTEN modulates GDNF/RET mediated chemotaxis and branching morphogenesis in the developing kidney. Dev Biol. 2007;307:290–299
  53. Tang MJ, Worley D, Sanicola M, Dressler GR. The RET-glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells. J Cell Biol. 1998;142:1337–1345
  54. Skinner MA, Safford SD, Reeves JG, Jackson ME, Freemerman AJ. Renal aplasia in humans is associated with RET mutations. Am J Hum Genet. 2008;82:344–351
  55. Lee DC, Chan KW, Chan SY. RET receptor tyrosine kinase isoforms in kidney function and disease. Oncogene. 2002;21:5582–5592
  56. Basson MA, Akbulut S, Watson-Johnson J, et al. Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell. 2005;8:229–239
  57. Kume T, Deng K, Hogan BL. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development. 2000;127:1387–1395
  58. Grieshammer U, Le M, Plump AS, et al. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev Cell. 2004;6:709–717
  59. Nakano T, Niimura F, Hohenfellner K, Miyakita E, Ichikawa I. Screening for mutations in BMP4 and FOXC1 genes in congenital anomalies of the kidney and urinary tract in humans. Tokai J Exp Clin Med. 2003;28:121–126
  60. Bertoli-Avella AM, Conte ML, Punzo F, et al. ROBO2 gene variants are associated with familial vesicoureteral reflux. J Am Soc Nephrol. 2008;19:825–831
  61. Costantini F, Shakya R. GDNF/Ret signaling and the development of the kidney. Bioessays. 2006;28:117–127
  62. Shakya R, Watanabe T, Costantini F. The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev Cell. 2005;8:65–74
  63. Yu OH, Murawski IJ, Myburgh DB, Gupta IR. Overexpression of RET leads to vesicoureteric reflux in mice. Am J Physiol Renal Physiol. 2004;287:F1123–F1130
  64. Tufro A, Teichman J, Woda C, Villegas G. Semaphorin3a inhibits ureteric bud branching morphogenesis. Mech Dev. 2008;125:558–568
  65. Gribouval O, Gonzales M, Neuhaus T, et al. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005;37:964–968
  66. Niimura F, Kon V, Ichikawa I. The renin-angiotensin system in the development of the congenital anomalies of the kidney and urinary tract. Curr Opin Pediatr. 2006;18:161–166
  67. Cano-Gauci DF, Song HH, Yang H, et al. Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. J Cell Biol. 1999;146:255–264
  68. Grisaru S, Cano-Gauci D, Tee J, Filmus J, Rosenblum ND. Glypican-3 modulates BMP- and FGF-mediated effects during renal branching morphogenesis. Dev Biol. 2001;231:31–46
  69. Stark K, Vainio S, Vassileva G, McMahon AP. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994;372:679–683
  70. Herzlinger D, Qiao J, Cohen D, Ramakrishna N, Brown AM. Induction of kidney epithelial morphogenesis by cells expressing Wnt-1. Dev Biol. 1994;166:815–818
  71. Torban E, Dziarmaga A, Iglesias D, et al. PAX2 activates WNT4 expression during mammalian kidney development. J Biol Chem. 2006;281:12705–12712
  72. Davies JA. Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat (Basel). 1996;156:187–201
  73. Bullock SL, Fletcher JM, Beddington RS, Wilson VA. Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev. 1998;12:1894–1906
  74. Merkel C, Karner C, Carroll T. Molecular regulation of kidney development: is the answer blowing in the Wnt?. Pediatr Nephrol. 2007;22:1825–1838
  75. Marose T, Merkel C, McMahon A, Carroll T. Beta-catenin is necessary to keep cells of ureteric bud/Wolffian duct epithelium in a precursor state. Dev Biol. 2008;314:112–126
  76. Yoshino K, Rubin JS, Higinbotham KG, et al. Secreted Frizzled-related proteins can regulate metanephric development. Mech Dev. 2001;102:45–55
  77. Gill P, Rosenblum N. Control of murine kidney development by sonic hedgehog and its GLI effectors. Cell Cycle. 2006;5:1426–1430
  78. Hu MC, Mo R, Bhella S, et al. GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis. Development. 2006;133:569–578
  79. Bose J, Grotewold L, Ruther U. Pallister-Hall syndrome phenotype in mice mutant for Gli3. Hum Mol Genet. 2002;11:1129–1135
  80. Kim PC, Mo R, Hui CC. Murine models of VACTERL syndrome: role of sonic hedgehog signaling pathway. J Pediatr Surg. 2001;36:381–384
  81. Yu J, Carroll TJ, McMahon AP. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development. 2002;129(22):5301–5312
  82. Oxburgh L, Chu GC, Michael SK, Robertson EJ. TGFbeta superfamily signals are required for morphogenesis of the kidney mesenchyme progenitor population. Development. 2004;131:4593–4605
  83. Michos O, Panman L, Vintersten K, et al. Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development. 2004;131:3401–3410
  84. Piscione TD, Phan T, Rosenblum ND. BMP7 controls collecting tubule cell proliferation and apoptosis via Smad1-dependent and -independent pathways. Am J Physiol Renal Physiol. 2001;280:F19–F33
  85. Hartwig S, Bridgewater D, Di Giovanni V, et al. BMP receptor ALK3 controls collecting system development. J Am Soc Nephrol. 2008;19:117–124
  86. Hartwig S, Hu MC, Cella C, et al. Glypican-3 modulates inhibitory Bmp2-Smad signaling to control renal development in vivo. Mech Dev. 2005;122:928–938
  87. Oxburgh L, Dudley AT, Godin RE, et al. BMP4 substitutes for loss of BMP7 during kidney development. Dev Biol. 2005;286:637–646
  88. Kazama I, Mahoney Z, Miner JH, et al. Podocyte-derived BMP7 is critical for nephron development. J Am Soc Nephrol. 2008;19:2181–2191
  89. Ueda H, Miyazaki Y, Matsusaka T, et al. Bmp in podocytes is essential for normal glomerular capillary formation. J Am Soc Nephrol. 2008;19:685–694
  90. Esquela AF, Lee SJ. Regulation of metanephric kidney development by growth/differentiation factor 11. Dev Biol. 2003;257:356–370
  91. Maeshima A, Vaughn DA, Choi Y, Nigam SK. Activin A is an endogenous inhibitor of ureteric bud outgrowth from the Wolffian duct. Dev Biol. 2006;295:473–485
  92. Michos O, Goncalves A, Lopez-Rios J, et al. Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis. Development. 2007;134:2397–2405
  93. Allen BL, Filla MS, Rapraeger AC. Role of heparan sulfate as a tissue-specific regulator of FGF-4 and FGF receptor recognition. J Cell Biol. 2001;155:845–858
  94. Plisov SY, Yoshino K, Dove LF, et al. TGF beta 2, LIF and FGF2 cooperate to induce nephrogenesis. Development. 2001;128:1045–1057
  95. Urban AE, Zhou X, Ungos JM, et al. FGF is essential for both condensation and mesenchymal-epithelial transition stages of pronephric kidney tubule development. Dev Biol. 2006;297:103–117
  96. Bates CM. Role of fibroblast growth factor receptor signaling in kidney development. Pediatr Nephrol. 2007;22:343–349
  97. Grieshammer U, Cebrian C, Ilagan R, et al. FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons. Development. 2005;132:3847–3857
  98. Poladia DP, Kish K, Kutay B, et al. Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol. 2006;291:325–339
  99. Hains D, Sims-Lucas S, Kish K, Saha M, McHugh K, et al. Role of fibroblast growth factor receptor 2 in kidney mesenchyme. Pediatr Res. 2008;64:592–598
  100. Chi L, Zhang S, Lin Y, et al. Sprouty proteins regulate ureteric branching by coordinating reciprocal epithelial Wnt11, mesenchymal Gdnf and stromal Fgf7 signalling during kidney development. Development. 2004;131:3345–3356
  101. El-Dahr SS, Aboudehen K, Dipp S. Bradykinin B2 receptor null mice harboring a Ser23-to-Ala substitution in the p53 gene are protected from renal dysgenesis. Am J Physiol Renal Physiol. 2008;295:F1404–F1413
  102. Rankin EB, Tomaszewski JE, Haase VH. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res. 2006;66(5):2576–2583
  103. Vanden Heuvel GB, Bodmer R, McConnell KR, Nagami GT, Igarashi P. Expression of a cut-related homeobox gene in developing and polycystic mouse kidney. Kidney Int. 1996;50:453–461
  104. Wilson PD. Mouse models of polycystic kidney disease. Curr Top Dev Biol. 2008;84:311–350
  105. Igarashi P, Shao X, McNally BT, Hiesberger T. Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney Int. 2005;68:1944–1947
  106. McGrath-Morrow S, Cho C, Molls R, et al. VEGF receptor 2 blockade leads to renal cyst formation in mice. Kidney Int. 2006;69:1741–1748
  107. Cheng HT, Kim M, Valerius MT, et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development. 2007;134:801–811
  108. Ryan G, Steele-Perkins V, Morris JF, Rauscher FJ, Dressler GR. Repression of Pax-2 by WT1 during normal kidney development. Development. 1995;121:867–875
  109. Wagner N, Wagner KD, Xing Y, Scholz H, Schedl A. The major podocyte protein nephrin is transcriptionally activated by the Wilms' tumor suppressor WT1. J Am Soc Nephrol. 2004;15:3044–3051
  110. Kanasaki K, Kanda Y, Palmsten K, et al. Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. Dev Biol. 2008;313:584–593
  111. Airik R, Bussen M, Singh MK, Petry M, Kispert A. Tbx18 regulates the development of the ureteral mesenchyme. J Clin Invest. 2006;116(3):663–674
  112. Caubit X, Lye CM, Martin E, et al. Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4. Development. 2008;135:3301–3310
  113. Alarcon P, Rodriguez-Seguel E, Fernandez-Gonzalez A, Rubio R, Gomez-Skarmeta JL. A dual requirement for Iroquois genes during Xenopus kidney development. Development. 2008;135:3197–3207
  114. Hong SK, Haldin CE, Lawson ND, et al. The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney. Proc Natl Acad Sci U S A. 2005;102:18473–18478
  115. Li DH, Chan T, Satow R, et al. The role of XTRAP-gamma in Xenopus pronephros development. Int J Dev Biol. 2005;49:401–408

 Dr. Reidy was supported in part by National Institutes of Health grant T32 DK007110 30.

PII: S0270-9295(09)00046-1

doi: 10.1016/j.semnephrol.2009.03.009

Seminars in Nephrology
Volume 29, Issue 4 , Pages 321-337 , July 2009