Molecular Insights into Segmentation along the Proximal–Distal Axis of the Nephron

Growing New Kidneys from Embryonic Cell Suspensions

“…However, if the mutation is present on both alleles, it leads to neonatal severe hyperparathyroidism, with profoundly symptomatic hypercalcemia, hypermagnesemia, and hyperparathyroidemia, and can be life-threatening unless the parathyroid glands are removed early in life. 4 Although FHH could largely be accounted for by a reset of the parathyroid calciostat, studies by Attie et al demonstrated that unusually low calcium clearance seen in FHH patients was caused by abnormal calcium sensing by the ascending limb of Henle's loop, in a fashion that was independent of systemic changes in PTH. 5 Subsequent to the cloning of the CaSR from parathyroid glands, the receptor was also identified from the rat kidney, 6 with the highest expression at the basolateral membrane of thick ascending limb cells and, to a lesser extent, in proximal convoluted tubules and collecting ducts.…”

“…2 By embryonic day (E) 10.5 in the mouse, the ureteric bud evaginates from the nephric duct and contacts the metanephric blastema to initiate the process of nephrogenesis. 3,4 Thus, tissue harvesting at E11.5 captures the developmental window when outgrowths of ureteric bud are branching and beginning to induce metanephric mesenchymal progenitor cells to differentiate. Evidence suggests that this midembryonic age of tissue harvesting gives superior results over late time points, probably because of greater tissue plasticity and growth potential as well as lower immunogenicity.…”

Renal organogenesis

“…An analysis of the minimal promoters of these proximal tubular genes revealed evidence for common transcriptional regulation from the MM, the MM is induced by the UB to condense around the tips of the forming branched ureteric epithelium and to undergo a mesenchyme-to-epithelial transition (MET) to form renal vesicles. 6,7 These small epithelial structures immediately begin to pattern as they proliferate and elongate to form the nephrons. 6,7 The process of MET is triggered via canonical Wnt signaling initiated by the secretion of Wnt9b from the ureteric tip, 8,9 which in turn upregulates Fgf8 and Wnt4.…”

Transcriptional control of terminal nephron differentiation

“…While there has been much progress in understanding the early steps involved in renal epithelial cell differentiation, a major gap remains in our knowledge of the factors that drive segmental nephron identity. Advances in studying model systems such as Xenopus laevis and zebrafish pronephros as well as systems in mice have been instrumental in understanding proximal-distal specification of the nephron (35,66,77).…”

“…DLL1 contributes via NOTCH2 in the specification of proximal tubule fate (12,35). Under the control of transcription factors BRN1 and Iroquois-class homeodomain proteins IRX 1-3, distal segments further extend and differentiate toward the distal tubule and Henle's loop (46,49,76) (Fig.…”