Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Principles of human and mouse nephron development

Nature Reviews Nephrology volume 18, pages 628–642 (2022)Cite this article

Subjects

Abstract

The mechanisms underlying kidney development in mice and humans is an area of intense study. Insights into kidney organogenesis have the potential to guide our understanding of the origin of congenital anomalies and enable the assembly of genetic diagnostic tools. A number of studies have delineated signalling nodes that regulate positional identities and cell fates of nephron progenitor and precursor cells, whereas cross-species comparisons have markedly enhanced our understanding of conserved and divergent features of mammalian kidney organogenesis. Greater insights into the complex cellular movements that occur as the proximal–distal axis is established have challenged our understanding of nephron patterning and provided important clues to the elaborate developmental context in which human kidney diseases can arise. Studies of kidney development in vivo have also facilitated efforts to recapitulate nephrogenesis in kidney organoids in vitro, by providing a detailed blueprint of signalling events, cell movements and patterning mechanisms that are required for the formation of correctly patterned nephrons and maturation of physiologically functional apparatus that are responsible for maintaining human health.

Key points

  • The gradual recruitment of nephron progenitors prefigures positional identities in the developing nephron.

  • Differentiating cells positioned along the proximal–distal axis of the early nephron display characteristics of mature cell types, indicating the existence of precursor–progeny relationships.

  • The process of nephrogenesis is intricately controlled by a number of signalling pathways, including those involving Notch, WNT, BMP and FGF.

  • Nephrogenesis is highly conserved between human and mouse, indicating an ancient evolutionary origin.

  • Podocytes and epithelial tubular components of the nephron display distinct transcriptional signatures and form at different times during nephrogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Nephron progenitor movements and a hierarchical ordering to the nephrogenic niche.
Fig. 2: The gradual recruitment model of nephrogenesis.
Fig. 3: The gradual recruitment of cells into the nephron and formation of putative precursor domains.
Fig. 4: Abundance of the Notch ligand JAG1 abundance throughout nephron development as a lineage map.

Similar content being viewed by others

References

  1. Schedl, A. Renal abnormalities and their developmental origin. Nat. Rev. Genet. 8, 791–802 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Short, K. M. et al. Global quantification of tissue dynamics in the developing mouse kidney. Dev. Cell 29, 188–202 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Hughson, M. D., Douglas-Denton, R., Bertram, J. F. & Hoy, W. E. Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int. 69, 671–678 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Bertram, J. F., Douglas-Denton, R. N., Diouf, B., Hughson, M. D. & Hoy, W. E. Human nephron number: implications for health and disease. Pediatr. Nephrol. 26, 1529–1533 (2011).

    Article  PubMed  Google Scholar 

  5. Keller, G., Zimmer, G., Mall, G., Ritz, E. & Amann, K. Nephron number in patients with primary hypertension. N. Engl. J. Med. 348, 101–108 (2003).

    Article  PubMed  Google Scholar 

  6. Hoy, W. E., Hughson, M. D., Bertram, J. F., Douglas-Denton, R. & Amann, K. Nephron number, hypertension, renal disease, and renal failure. J. Am. Soc. Nephrol. 16, 2557–2564 (2005).

    Article  PubMed  Google Scholar 

  7. Luyckx, V. A., Shukha, K. & Brenner, B. M. Low nephron number and its clinical consequences. Rambam Maimonides Med. J. 2, e0061 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Luyckx, V. A. & Brenner, B. M. Clinical consequences of developmental programming of low nephron number. Anat. Rec. 303, 2613–2631 (2020).

    Article  Google Scholar 

  9. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet 395, 709–733 (2020).

    Article  Google Scholar 

  10. Carney, E. F. The impact of chronic kidney disease on global health. Nat. Rev. Nephrol. 16, 251–251 (2020).

    Article  PubMed  Google Scholar 

  11. Saxen, L. Organogenesis of the Kidney (Cambridge Univ. Press, 1987).

  12. Rumballe, B. A. et al. Nephron formation adopts a novel spatial topology at cessation of nephrogenesis. Dev. Biol. 360, 110–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lindström, N. O. et al. Conserved and divergent features of human and mouse kidney organogenesis. J. Am. Soc. Nephrol. 29, 785–805 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cullen-McEwen, L., Sutherland, M. R. & Black, M. J. in Kidney Development, Disease, Repair and Regeneration (ed. Little, M.) 27–40 (Elsevier, 2016).

  15. Jarmas, A. E., Brunskill, E. W., Chaturvedi, P., Salomonis, N. & Kopan, R. Progenitor translatome changes coordinated by Tsc1 increase perception of Wnt signals to end nephrogenesis. Nat. Commun. 12, 6332 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Davies, J. A. & Garrod, D. R. Induction of early stages of kidney tubule differentiation by lithium ions. Dev. Biol. 167, 50–60 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Moore, M. W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Barak, H. et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22, 1191–1207 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Das, A. et al. Stromal-epithelial crosstalk regulates kidney progenitor cell differentiation. Nat. Cell Biol. 15, 1035–1044 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brown, A. C., Muthukrishnan, S. D. & Oxburgh, L. A synthetic niche for nephron progenitor cells. Dev. Cell 34, 229–241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lindström, N. O., Carragher, N. O. & Hohenstein, P. The PI3K pathway balances self-renewal and differentiation of nephron progenitor cells through β-catenin signaling. Stem Cell Rep. 4, 551–560 (2015).

    Article  CAS  Google Scholar 

  22. Mao, Y., Francis-West, P. & Irvine, K. D. Fat4/Dchs1 signaling between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching. Development 142, 2574–2585 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McNeill, H. & Reginensi, A. Lats1/2 regulate Yap/Taz to control nephron progenitor epithelialization and inhibit myofibroblast formation. J. Am. Soc. Nephrol. 28, 852–861 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Ihermann-Hella, A. et al. Dynamic MAPK/ERK activity sustains nephron progenitors through niche regulation and primes precursors for differentiation. Stem Cell Rep. 11, 912–928 (2018).

    Article  CAS  Google Scholar 

  25. Ramalingam, H. et al. Disparate levels of beta-catenin activity determine nephron progenitor cell fate. Dev. Biol. 440, 13–21 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Majumdar, A., Vainio, S., Kispert, A., McMahon, J. & McMahon, A. P. Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130, 3175–3185 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Carroll, T. J., Park, J. S., Hayashi, S., Majumdar, A. & McMahon, A. P. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev. Cell 9, 283–292 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Levinson, R. S. et al. Foxd1-dependent signals control cellularity in the renal capsule, a structure required for normal renal development. Development 132, 529–539 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Oxburgh, L. et al. BMP4 substitutes for loss of BMP7 during kidney development. Dev. Biol. 286, 637–646 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Kuure, S., Popsueva, A., Jakobson, M., Sainio, K. & Sariola, H. Glycogen synthase kinase-3 inactivation and stabilization of beta-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes. J. Am. Soc. Nephrol. 18, 1130–1139 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Park, J.-S., Valerius, M. T. & McMahon, A. P. Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development. Development 134, 2533–2539 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Boyle, S. C., Kim, M., Valerius, M. T., McMahon, A. P. & Kopan, R. Notch pathway activation can replace the requirement for Wnt4 and Wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development 138, 4245–4254 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Karner, C. M. et al. Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development. Development 138, 1247–1257 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Self, M. et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J. 25, 5214–5228 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Narlis, M., Grote, D., Gaitan, Y., Boualia, S. K. & Bouchard, M. Pax2 and Pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J. Am. Soc. Nephrol. 18, 1121–1129 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Park, J.-S. et al. Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev. Cell 23, 637–651 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Basta, J. M., Robbins, L., Kiefer, S. M., Dorsett, D. & Rauchman, M. Sall1 balances self-renewal and differentiation of renal progenitor cells. Development 141, 1047–1058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu, J., Liu, H., Park, J. S., Lan, Y. & Jiang, R. Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis. Development 141, 1442–1452 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xu, J. et al. Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Dev. Cell 31, 434–447 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. O’Brien, L. L. et al. Differential regulation of mouse and human nephron progenitors by the six family of transcriptional regulators. Development 143, 595–608 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. O’Brien, L. L. et al. Transcriptional regulatory control of mammalian nephron progenitors revealed by multi-factor cistromic analysis and genetic studies. PLoS Genet. 14, e1007181 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Guo, Q. et al. A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells. eLife 10, e64444 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. O’Brien, L. L. Nephron progenitor cell commitment: striking the right balance. Semin. Cell Dev. Biol. 91, 94–103 (2019).

    Article  PubMed  CAS  Google Scholar 

  44. Tomita, M. et al. Bmp7 maintains undifferentiated kidney progenitor population and determines nephron numbers at birth. PLoS ONE 8, e73554 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dudley, A. T., Lyons, K. M. & Robertson, E. J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 9, 2795–2807 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Fuchs, E. & Chen, T. A matter of life and death: self-renewal in stem cells. EMBO Rep. 14, 39–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, S. et al. Intrinsic age-dependent changes and cell-cell contacts regulate nephron progenitor lifespan. Dev. Cell 35, 49–62 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Lindström, N. O. et al. Conserved and divergent features of mesenchymal progenitor cell types within the cortical nephrogenic niche of the human and mouse kidney. J. Am. Soc. Nephrol. 29, 806–824 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Boyle, S. et al. Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev. Biol. 313, 234–245 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Kobayashi, A. et al. Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3, 169–181 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lindström, N. O. et al. Progressive recruitment of mesenchymal progenitors reveals a time-dependent process of cell fate acquisition in mouse and human nephrogenesis. Dev. Cell 45, 651–660.e4 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Menon, R. et al. Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney. Development 145, dev164038 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Combes, A. N. et al. Single cell analysis of the developing mouse kidney provides deeper insight into marker gene expression and ligand-receptor crosstalk. Development 146, dev178673 (2019).

    Article  PubMed  Google Scholar 

  54. Hochane, M. et al. Single-cell transcriptomics reveals gene expression dynamics of human fetal kidney development. PLoS Biol. 17, e3000152 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Tran, T. et al. In vivo developmental trajectories of human podocyte inform in vitro differentiation of pluripotent stem cell-derived podocytes. Dev. Cell 50, 102–116.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Little, M. H. et al. A high-resolution anatomical ontology of the developing murine genitourinary tract. Gene Expr. Patterns 7, 680–699 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Georgas, K. et al. Analysis of early nephron patterning reveals a role for distal RV proliferation in fusion to the ureteric tip via a cap mesenchyme-derived connecting segment. Dev. Biol. 332, 273–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Lindström, N. O. et al. Conserved and divergent molecular and anatomic features of human and mouse nephron patterning. J. Am. Soc. Nephrol. 29, 825–840 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Brown, A. C. et al. Role for compartmentalization in nephron progenitor differentiation. Proc. Natl Acad. Sci. USA 110, 4640–4645 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mugford, J. W., Yu, J., Kobayashi, A. & McMahon, A. P. High-resolution gene expression analysis of the developing mouse kidney defines novel cellular compartments within the nephron progenitor population. Dev. Biol. 333, 312–323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. O’Brien, L. L. et al. Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment. eLife 7, e40392 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Packard, A. et al. Luminal mitosis drives epithelial cell dispersal within the branching ureteric bud. Dev. Cell 27, 319–330 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Combes, A. N., Lefevre, J. G., Wilson, S., Hamilton, N. A. & Little, M. H. Cap mesenchyme cell swarming during kidney development is influenced by attraction, repulsion, and adhesion to the ureteric tip. Dev. Biol. 418, 297–306 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Lawlor, K. T. et al. Nephron progenitor commitment is a stochastic process influenced by cell migration. eLife 8, e41156 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Carl Huber, G. On the development and shape of uriniferous tubules of certain of the higher mammals. Am. J. Anat. 4, 1–98 (1905).

    Article  Google Scholar 

  66. Rienhoff, W. F. Development and growth of the metanephros or permanent kidney in chick embryos (eight to ten days’ incubation). Johns Hopkins Hosp. Bull. 33, 392–405 (1922).

    Google Scholar 

  67. Lindström, N. O. et al. Spatial transcriptional mapping of the human nephrogenic program. Dev. Cell 56, 2381–2398.e6 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Lindström, N. O. et al. Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron. eLife 3, e04000 (2015).

    Article  PubMed  Google Scholar 

  69. Miao, Z. et al. Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat. Commun. 12, 2277 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Naganuma, H. et al. Molecular detection of maturation stages in the developing kidney. Dev. Biol. 470, 62–73 (2021).

    Article  CAS  PubMed  Google Scholar 

  71. Cannoodt, R., Saelens, W. & Saeys, Y. Computational methods for trajectory inference from single-cell transcriptomics. Eur. J. Immunol. 46, 2496–2506 (2016).

    Article  CAS  PubMed  Google Scholar 

  72. McCormick, J. A. & Ellison, D. H. Distal convoluted tubule. Compr. Physiol. 5, 45–98 (2015).

    PubMed  PubMed Central  Google Scholar 

  73. Palmer, L. G. & Frindt, G. Na+ and K+ transport by the renal connecting tubule. Curr. Opin. Nephrol. Hypertens. 16, 477–483 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Dantzler, W. H., Layton, A. T., Layton, H. E. & Pannabecker, T. L. Urine-concentrating mechanism in the inner medulla: function of the thin limbs of the loops of Henle. Clin. J. Am. Soc. Nephrol. 9, 1781–1789 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Bell, P. D., Lapointe, J. Y. & Peti-Peterdi, J. Macula densa cell signaling. Annu. Rev. Physiol. 65, 481–500 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Peti-Peterdi, J. & Harris, R. C. Macula densa sensing and signaling mechanisms of renin release. J. Am. Soc. Nephrol. 21, 1093–1096 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Sparks, M. A., Crowley, S. D., Gurley, S. B., Mirotsou, M. & Coffman, T. M. Classical renin-angiotensin system in kidney physiology. Compr. Physiol. 4, 1201–1228 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Ransick, A. et al. Single-cell profiling reveals sex, lineage, and regional diversity in the mouse kidney. Dev. Cell 51, 399–413.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen, L., Chou, C.-L. & Knepper, M. A. Targeted single-cell RNA-seq identifies minority cell types of kidney distal nephron. J. Am. Soc. Nephrol. 32, 886–896 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  80. Stark, K., Vainio, S., Vassileva, G. & McMahon, A. P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  81. Tanigawa, S. et al. Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism. Dev. Biol. 352, 58–69 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Burn, S. F. et al. Calcium/NFAT signalling promotes early nephrogenesis. Dev. Biol. 352, 288–298 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kobayashi, A. et al. Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development 132, 2809–2823 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Grieshammer, U. et al. FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons. Development 132, 3847–3857 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Chung, E., Deacon, P., Marable, S., Shin, J. & Park, J.-S. Notch signaling promotes nephrogenesis by downregulating Six2. Development 143, 3907–3913 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Estrach, S., Ambler, C. A., Lo Celso, C., Hozumi, K. & Watt, F. M. Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 133, 4427–4438 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Katoh, M. & Katoh, M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int. J. Mol. Med. 17, 681–685 (2006).

    CAS  PubMed  Google Scholar 

  88. Liu, Z. et al. The extracellular domain of notch2 increases its cell-surface abundance and ligand responsiveness during kidney development. Dev. Cell 25, 585–598 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Schneider, J., Arraf, A. A., Grinstein, M., Yelin, R. & Schultheiss, T. M. Wnt signaling orients the proximal-distal axis of chick kidney nephrons. Development 142, 2686–2695 (2015).

    CAS  PubMed  Google Scholar 

  90. Karner, C. M. et al. Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat. Genet. 41, 793–799 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Deacon, P., Concodora, C. W., Chung, E. & Park, J.-S. β-catenin regulates the formation of multiple nephron segments in the mouse kidney. Sci. Rep. 9, 15915 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Farin, H. F. et al. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530, 340–343 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Sagner, A. & Briscoe, J. Establishing neuronal diversity in the spinal cord: a time and a place. Development 146, dev182154 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Heliot, C. et al. HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2. Development 140, 873–885 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Lindner, T. H. et al. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum. Mol. Genet. 8, 2001–2008 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Weng, J. P. et al. Hepatocyte nuclear factor-1 beta (MODY5) gene mutations in Scandinavian families with early-onset diabetes or kidney disease or both. Diabetologia 43, 131–132 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Nakai, S. et al. Crucial roles of Brn1 in distal tubule formation and function in mouse kidney. Development 130, 4751–4759 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Massa, F. et al. Hepatocyte nuclear factor 1β controls nephron tubular development. Development 140, 886–896 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Reggiani, L., Raciti, D., Airik, R., Kispert, A. & Brändli, A. W. The prepattern transcription factor Irx3 directs nephron segment identity. Genes Dev. 21, 2358–2370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Corkins, M. E. et al. A comparative study of cellular diversity between the Xenopus pronephric and mouse metanephric nephron. Preprint at bioRxiv https://doi.org/10.1101/2022.01.11.475739 (2022).

    Article  Google Scholar 

  101. Lebel, M. et al. The Iroquois homeobox gene Irx2 is not essential for normal development of the heart and midbrain-hindbrain boundary in mice. Mol. Cell. Biol. 23, 8216–8225 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Marneros, A. G. AP-2β/KCTD1 control distal nephron differentiation and protect against renal fibrosis. Dev. Cell 54, 348–366.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, Y., Cheng, C. N., Verdun, V. A. & Wingert, R. A. Zebrafish nephrogenesis is regulated by interactions between retinoic acid, mecom, and Notch signaling. Dev. Biol. 386, 111–122 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Grote, D., Souabni, A., Busslinger, M. & Bouchard, M. Pax 2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney. Development 133, 53–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Grote, D. et al. Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction. PLoS Genet. 4, e1000316 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Chen, L. et al. Transcriptomes of major renal collecting duct cell types in mouse identified by single-cell RNA-seq. Proc. Natl Acad. Sci. USA 114, E9989–E9998 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Howden, S. E. et al. Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk. Cell Stem Cell 28, 671–684.e6 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. Barker, N. et al. Lgr5+ve stem/progenitor cells contribute to nephron formation during kidney development. Cell Rep. 2, 540–552 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Yu, J. et al. A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136, 161–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Portilla, D. et al. Metabolomic study of cisplatin-induced nephrotoxicity. Kidney Int. 69, 2194–2204 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Liu, J. et al. Renoprotective and immunomodulatory effects of GDF15 following AKI Invoked by Ischemia-reperfusion injury. J. Am. Soc. Nephrol. 31, 701–715 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chevalier, R. L. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. Am. J. Physiol. Renal Physiol. 311, F145–F161 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Marable, S. S., Chung, E., Adam, M., Potter, S. S. & Park, J.-S. S. Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome. JCI Insight 3, e97497 (2018).

    Article  PubMed Central  Google Scholar 

  115. Marable, S. S., Chung, E. & Park, J.-S. Hnf4a is required for the development of Cdh6-expressing progenitors into proximal tubules in the mouse kidney. J. Am. Soc. Nephrol. 31, 2543–2558 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hansen, S. K. et al. Genetic evidence that HNF-1α-dependent transcriptional control of HNF-4α is essential for human pancreatic β cell function. J. Clin. Invest. 110, 827–833 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hamilton, A. J. et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. J. Med. Genet. 51, 165–169 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. de Boer, I. H. et al. Rationale and design of the kidney precision medicine project. Kidney Int. 99, 498–510 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Lake, B. B. et al. An atlas of healthy and injured cell states and niches in the human kidney. Preprint at bioRxiv https://doi.org/10.1101/2021.07.28.454201 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Tian, J. M. & Schibler, U. Tissue-specific expression of the gene encoding hepatocyte nuclear factor 1 may involve hepatocyte nuclear factor 4. Genes Dev. 5, 2225–2234 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. Eeckhoute, J., Formstecher, P. & Laine, B. Hepatocyte nuclear factor 4alpha enhances the hepatocyte nuclear factor 1α-mediated activation of transcription. Nucleic Acids Res. 32, 2586–2593 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen, L. et al. HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine. Development 146, dev179432 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dudley, A. T. & Robertson, E. J. Overlapping expression domains of bone morphogenetic protein family members potentially account for limited tissue defects in BMP7 deficient embryos. Dev. Dyn. 208, 349–362 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Luo, G. et al. BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev. 9, 2808–2820 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Blank, U. et al. An in vivo reporter of BMP signaling in organogenesis reveals targets in the developing kidney. BMC Dev. Biol. 8, 86 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Miyazaki, Y., Oshima, K., Fogo, A., Hogan, B. L. M. & Ichikawa, I. Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J. Clin. Invest. 105, 863–873 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Oxburgh, L., Brown, A. C., Fetting, J. & Hill, B. BMP signaling in the nephron progenitor niche. Pediatr. Nephrol. 26, 1491–1497 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Nishinakamura, R. & Sakaguchi, M. BMP signaling and its modifiers in kidney development. Pediatr. Nephrol. 29, 681–686 (2014).

    Article  PubMed  Google Scholar 

  129. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for notch1. Nat. Genet. 16, 243–251 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Spinner, N. B. et al. Jagged1 mutations in Alagille syndrome. Hum. Mutat. 17, 18–33 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Penton, A. L., Leonard, L. D. & Spinner, N. B. Notch signaling in human development and disease. Semin. Cell Dev. Biol. 23, 450–457 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mukherjee, M., Fogarty, E., Janga, M. & Surendran, K. Notch signaling in kidney development, maintenance, and disease. Biomolecules 9, 1–23 (2019).

    Article  CAS  Google Scholar 

  133. Duvall, K. et al. Revisiting the role of notch in nephron segmentation confirms a role for proximal fate selection during mouse and human nephrogenesis. Development 149, dev200446 (2022).

    Article  CAS  Google Scholar 

  134. Cheng, H.-T. et al. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 134, 801–811 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Chung, E., Deacon, P. & Park, J.-S. Notch is required for the formation of all nephron segments and primes nephron progenitors for differentiation. Development 144, 4530–4539 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Chen, L. & Al-Awqati, Q. Segmental expression of Notch and Hairy genes in nephrogenesis. Am. J. Physiol. Renal Physiol. 288, F939–F952 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Liu, Z. et al. The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis. Development 142, 2452–2463 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ong, C.-T. et al. Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. J. Biol. Chem. 281, 5106–5119 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Cheng, H.-T. et al. Gamma-secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podocyte and proximal tubule formation in developing mouse kidney. Development 130, 5031–5042 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Baker, C. M., Verstuyf, A., Jensen, K. B. & Watt, F. M. Differential sensitivity of epidermal cell subpopulations to beta-catenin-induced ectopic hair follicle formation. Dev. Biol. 343, 40–50 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sjöqvist, M. & Andersson, E. R. Do as I say, Not(ch) as I do: lateral control of cell fate. Dev. Biol. 447, 58–70 (2019).

    Article  PubMed  CAS  Google Scholar 

  142. Seymour, P. A. et al. Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors. Dev. Cell 52, 731–747.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Shimojo, H. et al. Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes Dev. 30, 102–116 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kageyama, R., Shimojo, H. & Isomura, A. Oscillatory control of Notch signaling in development. Adv. Exp. Med. Biol. 1066, 265–277 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Hicks, C. et al. Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nat. Cell Biol. 2, 515–520 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Maezawa, Y. et al. Loss of the podocyte-expressed transcription factor Tcf21/Pod1 results in podocyte differentiation defects and FSGS. J. Am. Soc. Nephrol. 25, 2459–2470 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kann, M. et al. Genome-wide analysis of Wilms’ tumor 1-controlled gene expression in podocytes reveals key regulatory mechanisms. J. Am. Soc. Nephrol. 26, 2097–2104 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Moriguchi, T. et al. MafB is essential for renal development and F4/80 expression in macrophages. Mol. Cell. Biol. 26, 5715–5727 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Berry, R. L. et al. Deducing the stage of origin of Wilms’ tumours from a developmental series of Wt1-mutant mice. Dis. Model. Mech. 8, 903–917 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Oliver, J. Nephrons and Kidneys (Hoeber, 1968).

  151. Takasato, M. et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526, 564–568 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Taguchi, A. et al. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell 14, 53–67 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Freedman, B. S. et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat. Commun. 6, 8715 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Morizane, R. et al. Nephron organoids derived from human pluripotent stem cells model kidney development and injury. Nat. Biotechnol. 33, 1193–1200 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to all members past and present in the Lindström laboratory, and to A. McMahon for his mentorship. J.S. is funded by a T32 training grant. M.A.A. and N.O.L. are funded by the University of Southern California, USA.

Author information

Author notes

  1. These authors contributed equally: Jack Schnell, MaryAnne Achieng.

Authors and Affiliations

  1. Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at University of Southern California, Los Angeles, CA, USA

    Jack Schnell, MaryAnne Achieng & Nils Olof Lindström

Authors
  1. Jack Schnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. MaryAnne Achieng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nils Olof Lindström
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Nils Olof Lindström.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Nephrology thanks Kieran Short and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Filopodia

Dynamic, thin cell-membrane protrusions associated with cell sensing and migration.

Lamellipodia

Dynamic, broad cell-membrane protrusions associated with cell migration.

Planar cell polarity

An axial dimension associated with the plane within an epithelium and elsewhere used in association with a pathway.

Maturity-onset diabetes of the young

A rare form of genetically linked diabetes with an early onset.

Chromatin immunoprecipitation

(ChIP). A laboratory technique used to isolate DNA bound by transcription factors and other DNA-binding proteins using antibodies against these proteins.

Fanconi renotubular syndrome

(FRTS). A rare disorder associated with nephron proximal tubules and their loss of function.

ChIP sequencing

A DNA sequencing analysis method for characterizing putative cis-regulatory DNA sequences bound by transcription factors and other DNA-binding proteins.

Lateral inhibition

A cell signalling process whereby a cell inhibits a neighbouring cell from activating a signalling event.

Lateral induction

A cell signalling process where a cell activates or allows a signal event to take place in a neighbouring cell.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schnell, J., Achieng, M. & Lindström, N.O. Principles of human and mouse nephron development. Nat Rev Nephrol 18, 628–642 (2022). https://doi.org/10.1038/s41581-022-00598-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-022-00598-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing