Formation of the nephric duct

Formation of the nephric duct The nephric duct originates from nephrogenic cords of intermediate mesoderm by a transition of the cells to epithelium in response to signals from somites and overlying ectoderm (reviewed in Reidy and Rosenblum 2009, Little and McMahon 2012, Khoshdel Rad et al. 2020). Initially, the nephric duct forms within in the pronephros, the first kidney structure, which comprises the nephric duct (the pronephric duct at this time) and connected tubules that empty into it. The second kidney structure, the mesonephros, then forms at the caudal end of the pronephros and contains a segment of the nephric duct, the mesonephric duct (also called the Wolffian duct), with connected proximal and distal tubules attached to nephrons and vascular glomeruli. The mesonephros fuses with the cloaca and contributes to the urinary bladder.
The metanephros then forms and persists as the functional adult kidney. The metanephros originates by the initiation of the ureteric bud from of the caudal end of the mesonephric duct, a process that is driven by molecular interactions between the nephric duct and the adjacent metanephric mesenchyme. The ureteric bud then branches and about a million nephrons, the functional filtration units of the kidney, are formed at the ureteric bud tips by an interaction between the ureteric bud and the metanephric mesenchyme.
The position of kidney formation is determined by the retinoic acid gradient acting through the HOXB4 homeobox transcription factor (inferred from mouse embryos in Preger-Ben Noon et al.2009, reviewed in Marcotte et al. 2014). PAX2, PAX8, and LHX1 are expressed early during the formation of the intermediate mesoderm. Subsequently, expression of LHX1 becomes restricted to the developing renal progenitors and is maintained by PAX2 and PAX8 (inferred from mouse homologs in Boualia et al. 2013). In the developing nephric duct, LHX1 acts with PAX2 and GATA3 to form a self-reinforcing regulatory module based on the mutual activation of LHX1 and GATA3 that drives formation of the nephric duct of the pronephros and mesonephros (inferred from mouse homologs in Boualia et al. 2013, reviewed in Marcotte et al. 2014). LHX1, GATA3, PAX2, and PAX8 then activate several genes involved in differentiation of the nephric duct including EMX2, EVI1, ID4, PLAC8, WFDC2, PCDH19, Nephronectin (NPNT), and the receptor tyrosine kinase RET (reviewed in Marcotte et al. 2014). Subsequent formation of the ureteric bud is regulated by the interaction between GDNF from the metanephric mesenchyme and RET (inferred from mouse homologs in Majumdar et al. 2003) and the interaction between integrin alpha8/beta1 (ITGA8) from the metanephric mesenchyme and NPNT (inferred from mouse homologs in Brandenberger et al. 2001).