Kidney development

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R-HSA-9830369
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Pathway
Species
Homo sapiens
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3/5
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Kidney development
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Kidney development begins at embryonic day 8.5 (E8.5) in mouse embryos, a time after gastrulation and formation of the intermediate mesoderm (reviewed in Marcotte et al. 2014, Smyth 2021, Schnell et al. 2022). Renal progenitors are specified within the intermediate mesoderm in the region between the 6th and 8th somites. The nephric duct then begins to form by mesenchymal to epithelial transitions of the renal progenitors and grows caudally to fuse with the bladder and urethra primordium (cloaca). The nephric duct induces the formation of mesonephric tubules in the adjacent nephric cord which form the mesonephros, an embryonic kidney in mammals that regresses and is supplanted by the metanephros. (In anamniotes such as frogs and fish, the mesonephros is the adult kidney and no metanephros forms.)
In mammals, the metanephros is initiated as the caudal region of the nephric cord forms metanephric mesenchyme which then interacts with the nephric duct to induce formation of the ureteric bud, the progenitor of the ureter. Branching of the ureteric bud forms ureter tips which induce nephron formation in the surrounding metanephric mesenchyme (reviewed in El-Dahr et al. 2008, O'Brien and McMahon 2014, Desgrange and Cereghini 2015, Chambers and Wingert 2020, Schnell et al. 2022).
Induction of kidney development in the intermediate mesoderm occurs by incompletely characterized signals from the adjacent ectoderm and lateral plate mesoderm. Notably, BMP activity from the lateral plate mesoderm can induce expression of the renal markers Pax2 and Lhx1.
Foxc1 and Foxc2 expressed in the paraxial mesoderm repress Lhx1 and prevent over-expansion of the intermediate mesoderm (Wilm et al. 2004). Conversely, Nodal signaling maintains Pax2 expression and prevents over-expansion of the paraxial mesoderm (Fleming et al. 2013). The rostral-caudal position of renal development appears to specified by the rostral-caudal gradient of retinoic acid acting through HoxB4 (Preger-Ben Noon et al. 2009) and limited caudally by HoxA6.
The combined expression of Pax2, Pax8, Lhx1, and Gata3 is the earliest observed marker of the renal lineage and these transcription factors, together with Emx2, form a self-reinforcing module that drives formation of the nephric duct. Nephronectin (Npnt) from the nephric duct interacts with integrin alpha8/beta1 (Itga8) on the metanephric mesenchyme and Ret located on the nephric duct interacts with Gdnf secreted by the metanephric mesenchyme to regulate formation and branching of the ureteric bud (reviewed in Marcotte et al. 2014). Signals from the tips of the ureteric bud then induce epithelialization of the metanephric mesenchyme and formation of nephrons, the basic filtration units of the kidney comprising the glomerulus, the proximal tubule, the loop of Henle, and the distal tubule (reviewed in Desgrange and Cereghini 2015). Canonical Wnt signaling from the ureteric bud appears to be the main inductive event: Wnt9b activates Wnt4 expression to epithelialize mesenchymal pre-tubular aggregates and Wnt9b also supports expression of Six2 to maintain a nephron progenitor pool in the cap mesenchyme.
Congenital anomalies of the kidney and urinary tract (CAKUT) comprise about 30% of antnatal congenital abnormalities and cause the majority of chronic kidney disease in children (reviewed in Costigan and Rosenblum 2022). Knowledge gained from studying kidney development is being used to generate kidney organoids in vitro with a goal of producing transplantable kidney tissue (reviewed in Kalejaiye et al. 2022, Safi et al. 2022, Trush and Takasato 2022, Shi et al. 2023).
Literature References
PubMed ID Title Journal Year
26378582 Nephron Patterning: Lessons from Xenopus, Zebrafish, and Mouse Studies

Desgrange, A, Cereghini, S

Cells 2015
35785592 Kidney organoid research: current status and applications

Trush, O, Takasato, M

Curr Opin Genet Dev 2022
19439491 Interplay between activin and Hox genes determines the formation of the kidney morphogenetic field

Preger-Ben Noon, E, Barak, H, Guttmann-Raviv, N, Reshef, R

Development 2009
36311696 Translating Organoids into Artificial Kidneys

Kalejaiye, TD, Barreto, AD, Musah, S

Curr Transplant Rep 2022
35869368 Principles of human and mouse nephron development

Schnell, J, Achieng, M, Lindström, NO

Nat Rev Nephrol 2022
19615554 Cell and molecular biology of kidney development

Reidy, KJ, Rosenblum, ND

Semin Nephrol 2009
22942910 Genetic controls and cellular behaviors in branching morphogenesis of the renal collecting system

Costantini, F

Wiley Interdiscip Rev Dev Biol 2012
36423515 Anatomy and embryology of congenital surgical anomalies: Congenital Anomalies of the Kidney and Urinary Tract

Costigan, CS, Rosenblum, ND

Semin Pediatr Surg 2022
15196959 The forkhead genes, Foxc1 and Foxc2, regulate paraxial versus intermediate mesoderm cell fate

Wilm, B, James, RG, Schultheiss, TM, Hogan, BL

Dev Biol 2004
36120564 Assessing kidney development and disease using kidney organoids and CRISPR engineering

Safi, W, Marco, A, Moya, D, Prado, P, Garreta, E, Montserrat, N

Front Cell Dev Biol 2022
26969971 Development of the Mammalian Kidney

McMahon, AP

Curr Top Dev Biol 2016
33820620 Development of the metanephric kidney

Smyth, IM

Curr Top Dev Biol 2021
33092489 Advances in understanding vertebrate nephrogenesis

Chambers, JM, Wingert, RA

Tissue Barriers 2020
22550230 Mammalian kidney development: principles, progress, and projections

Little, MH, McMahon, AP

Cold Spring Harb Perspect Biol 2012
24104595 Gene regulatory network of renal primordium development

Marcotte, M, Sharma, R, Bouchard, M

Pediatr Nephrol 2014
23533180 A role for Vg1/Nodal signaling in specification of the intermediate mesoderm

Fleming, BM, Yelin, R, James, RG, Schultheiss, TM

Development 2013
18287399 Transcriptional control of terminal nephron differentiation

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

Am J Physiol Renal Physiol 2008
19906853 Advances in early kidney specification, development and patterning

Dressler, GR

Development 2009
25194660 Induction and patterning of the metanephric nephron

O'Brien, LL, McMahon, AP

Semin Cell Dev Biol 2014
37460630 Directed differentiation of ureteric bud and collecting duct organoids from human pluripotent stem cells

Shi, M, Fu, P, Bonventre, JV, McCracken, KW

Nat Protoc 2023
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kidney development (0001822)
Authored
May, B  (2023-03-08)
Created
May, B  (2023-03-09)
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