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First published online 9 January 2008
doi: 10.1242/dev.001081

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Development of the renal glomerulus: good neighbors and good fences

¹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Division of Nephrology, St. Michael's Hospital, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
² Department of Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

View larger version (29K): [in this window] [in a new window]   Fig. 1. A schematic of kidney development. (A) Cross section of an E11.5 mouse embryonic kidney at induction. Mesenchyme (blue) condenses around the two branches of the ureteric bud (UB, red), and receives an inductive signal from it, which includes Wnt9b (Carroll et al., 2005). (B) Some of the mesenchymal condensate forms a pre-tubular aggregate (PTA) adjacent to the underside of each branch of the UB. This aggregate undergoes a mesenchymal to epithelial transformation, under the influence of Wnt4 (Stark et al., 1994), to form a simple tubule called a renal vesicle (RV). (C) The RV then undergoes segmentation to form the nephron, which consists of the glomerulus (G) at the proximal end, and the tubular component [the proximal (P) tubule, the ascending and descending loops of Henle (not shown) and the distal (D) tubule]. The distal tubule connects to the UB, which itself transforms into collecting ducts that conduct urine out of the kidney. (D) A mature nephron (not to scale), showing capillary loops (red) inside the glomerulus, and the glomerular basement membrane (GBM, green) between podocytes (blue) and the capillaries (mesangial cells are not shown). The distal segment of the nephron (light blue) connects to a collecting duct (red) that is derived from the UB. (E) To form the mature kidney, the process shown in A-D is reiterated by continued branching of the UB and its derivatives (red). Each of the tips of the UB derivatives continue to induce new nephrons (blue) from a population of progenitor cells present at the periphery of the developing kidney, known as the nephrogenic zone (NZ). Nephrons are located in the cortex (unshaded; with some segments dipping into the medulla), whereas collecting ducts (red) derived from the UB extend from the cortex to the medulla (green) and the medullary papilla (pink), where they drain into the ureter. Reproduced, with permission, from Kreidberg (Kreidberg, 2006).

View larger version (154K): [in this window] [in a new window]   Fig. 2. Histology of glomerular development. (A-C) Toluidine blue-stained sections from newborn mouse kidneys. (A) S-shaped body. P, podocyte progenitors; GC, glomerular cleft. A capillary loop is present in the cleft. B, Bowman's capsule. (B) Immature glomerulus showing the `bowl'-shaped arrangement of the podocytes. Cap, capillary loops. (C) Mature glomerulus. P, podocytes; M, mesangial cells. (D) Scanning electron micrograph of the interior of an adult rat glomerulus showing interdigitating foot processes (FP) encompassing capillary loops. P, podocyte cell body. (E) Transmission electron micrograph of a newborn mouse glomerulus. FP, foot processes; GBM, glomerular basement membrane; End, endothelial cell; Cap, capillary lumen. (F) Transmission electron micrograph from an 3 integrin mutant newborn mouse kidney, showing malformed foot processes and fragmented glomerular basement membrane. Image in D kindly provided by Wilhelm Kriz (Heidelberg).

View larger version (17K): [in this window] [in a new window]   Fig. 3. A theoretical model of podocyte maturation and foot process assembly. (A) Two podocytes (blue) begin as discs of columnar epithelial cells, which are attached along their entire lateral membranes. (B) Podocytes lose their lateral cell attachments except at their base, and begin to interdigitate along the basal aspect of the lateral membrane. (C) Podocyte cell bodies become independent of each other, but remain attached through interdigitated foot processes.

View larger version (33K): [in this window] [in a new window]   Fig. 4. Schematic of a mature glomerulus in cross section. Fewer capillary loops are shown than normal for clarity, and the size of cells are exaggerated in proportion to the overall size of the glomerulus. The four major cell types of the glomerulus are the Bowman's capsule (BC) or parietal epithelium (gray), podocytes (P, blue) or visceral epithelium, mesangial cells (M, orange) and endothelial cells (E, red). The mature glomerulus is encompassed by the Bowman's capsule. The glomerulus comprises a self-contained network of capillary loops (C, red), with mesangial cells forming a nexus at the base of the capillary network. The glomerular basement membrane (GBM, green) divides the glomerulus into two compartments, an inner one containing the capillaries and the mesangial cells, and an outer one containing podocytes and the space into which the filtrate passes. The glomerulus remains connected to the remainder of the nephron through an opening in the Bowman's capsule that connects the glomerulus to the proximal tubule, shown on the right. The arrows in the capillaries indicate the flow of blood in and out of the glomerulus. Also omitted for clarity is the branching of the single capillary loop into the multiple loops within each glomerulus.

View larger version (36K): [in this window] [in a new window]   Fig. 5. Schematic of the slit diaphragm and other important proteins involved in maintaining foot process assembly. Many proteins are omitted to emphasize the two major complexes of proteins discussed in the text. For clarity, one complex is shown within the left foot process, the other in the right foot process. Two adjacent foot processes are shown. In the left foot process is the nephrin-FYN-NCK complex, associated with an actin filament. In the right foot process, the nephrin-podocin-CD2AP complex and the integrin-linked kinase (ILK)-parvin-pinch complex associated with both 3β1 integrin and nephrin are shown. Synaptopodin and -actinin 4 are also shown associated with the cytoskeleton, the latter also with integrins. Nephrin and FAT are shown as two major proteins that bridge the space between adjacent foot processes, although, as noted in the text, nephrin also associates with Neph proteins. The integrin and dystroglycan complexes are shown in each foot process. P, phosphorylation (see key for other abbreviations used in the figure).

View larger version (146K): [in this window] [in a new window]   Fig. 6. A comparison of normal and 3 integrin mutant mouse glomerular development. (A,C,E) Successive stages of normal mouse glomerular development. (A) Capillary loop stage, at which time the podocytes (P) still resemble a columnar epithelium and are forming a `bowl'-shaped sheet into which capillaries are beginning to branch from a single loop into multiple loops. Scale bar: 8 µm. (B) The capillary loop stage is relatively normal in the absence of 3β1 integrin. (C) Intermediate stage of glomerular development, where podocytes have begun to lose their cell-cell attachments and migrate around capillary loops. Mesangial cells (darker nuclei) are present in the middle of the glomerulus, where podocytes are beginning to encompass capillary loops. (D) In the absence of 3β1 integrin, podocytes have completely lost cell-cell attachments, and their cell bodies appear to be connected by a thin `neck' to the basement membrane. (E) Mature normal glomerulus. (F) In the absence of 3β1 integrin, abnormally wide capillary loops are present, and podocytes are mainly situated in the peripherly of the glomerulus. GC, glomerular cleft. [Reproduced from Kreidberg et al. (Kreidberg et al., 1996).]

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