Nephron development

Stable Identifier
R-HSA-9831926
Type
Pathway
Species
Homo sapiens
ReviewStatus
3/5
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A nephron of an amniote such as mouse or human comprises the glomerulus where small molecules are filtered out of the blood, the proximal tubule and the loop of Henle where small molecules are selectively reabsorbed, the thick ascending limb, the macula densa, the distal convoluted tubule, the connecting tubule, and the collecting duct which drains into the ureter.
Initiation of nephron development occurs at the termini of the branches of the ureteric bud where cells of the ureteric bud interact with cells of the metanephric mesenchyme. Rather than differentiating in place, analysis of cellular migration indicates that progenitors are recruited from the mesenchyme to the developing epithelial elements of the nephron (Lindstrom et al. 2018). The transcriptional program that operates during human nephrogenesis has been mapped in extraordinary detail (Lindstrom et al. 2021). WNT9B secreted by the ureteric bud induces a subset of renal progenitor cells to aggregate and express WNT4, which causes the pre-tubular aggregates to further undergo a mesenchymal to epithelial transition to form renal vesicles (inferred from mouse embryos in Park et al. 2007, reviewed in El-Dahr et al. 2008, Costantini and Kopan 2010, Desgrange and Cereghini 2015). A subset of renal progenitor cells express SIX2 and respond to WNT9B by proliferating to maintain a renewing population of renal progenitors. The reason for the difference in responses may be the local concentration of WNT9B (inferred from mouse embryos in Ramalingam et al. 2018) or the presence of the transcription factor SIX2 (inferred from mouse embryos in Karner et al. 2011).
The renal vesicle becomes polarized early. The distal region contains a gene regulatory network containing LHX1, POU3F3 (BRN1), DLL1, and JAG1. LHX1 is required for proximo-distal differentiation (inferred from mouse embryos in Kobayashi et al. 2005) and POU3F3 participates in elongation of the loop of Henle and formation of the distal convoluted tubule (inferred from mouse embryos in Nakai et al. 2003). The proximal region of the renal vesicle expresses WT1, which directly represses PAX2 to enable formation of podocytes (inferred from mouse homologs in Ryan et al. 1995). The renal vesicle develops into the comma-shaped body in which HNF1B in the distal region activates NOTCH pathway components DLL1, JAG1, and LFNG (inferred from mouse embryos in Heliot et al. 2013). The comma-shaped body in turn develops into the S-shaped body in which HNF1B activates IRX1 and IRX2 in the intermediate region (inferred from mouse embryos in Heliot et al. 2013). Podocytes, the proximal tubule, the intermediate tubule, and the distal tubule then differentiate.
Literature References
PubMed ID Title Journal Year
21350016 Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development

Oliver, G, Chen, C, Lum, L, Carroll, TJ, Das, A, Self, M, Ma, Z, Karner, CM

Development 2011
26378582 Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies

Desgrange, A, Cereghini, S

Cells 2015
15930111 Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development

Carroll, TJ, McMahon, AP, Mendelsohn, CL, Kwan, KM, Behringer, RR, Kobayashi, A

Development 2005
29705331 Disparate levels of beta-catenin activity determine nephron progenitor cell fate

Basta, J, Valerius, MT, Robbins, L, Brown, AC, Carroll, TJ, Das, A, Rauchman, M, McMahon, AP, Oxburgh, L, Fessler, AR, Ramalingam, H

Dev Biol 2018
17537789 Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development

Valerius, MT, Park, JS, McMahon, AP

Development 2007
18287399 Transcriptional control of terminal nephron differentiation

Saifudeen, Z, Aboudehen, K, El-Dahr, SS

Am J Physiol Renal Physiol 2008
29870722 Progressive Recruitment of Mesenchymal Progenitors Reveals a Time-Dependent Process of Cell Fate Acquisition in Mouse and Human Nephrogenesis

Smith, AD, Parvez, RK, Ransick, A, Ruffins, SW, Guo, J, Grubbs, B, Suh, G, Kim, AD, Lindström, NO, Thornton, ME, McMahon, JA, McMahon, AP, Rutledge, EA, Tran, T, De Sena Brandine, G

Dev Cell 2018
20493806 Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development

Costantini, F, Kopan, R

Dev Cell 2010
12925600 Crucial roles of Brn1 in distal tubule formation and function in mouse kidney

Miura, Y, Nishi, M, Ito, S, Noda, T, Minowa, O, Sato, H, Ogawa, M, Nakai, S, Jishage, K, Sugitani, Y

Development 2003
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