Kidney development

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. Conversely, Nodal signaling maintains Pax2 expression and prevents over-expansion of the paraxial mesoderm. 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).