Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development

Abstract

The two major components of the kidney, the collecting system and the nephron, have different developmental histories. The collecting system arises by the reiterated branching of a simple epithelial tube, while the nephron forms from a cloud of mesenchymal cells that coalesce into epithelial vesicles. Each develops into a morphologically complex and highly differentiated structure, and together they provide essential filtration and resorption functions. In this review, we will consider their embryological origin and the genes controlling their morphogenesis, patterning, and differentiation, with a focus on recent advances in several areas.

Figure 1. Development of nephric duct and renal collecting duct system

A, Left, diagram of E9.5 embryo, showing nephric duct (green, ND) and nephrogenic cord (blue, NC) in caudal region of embryo. Right, schematic cross-section showing the ND, NC, neural tube (NT), somites (S), and lateral plate mesoderm (LPM). B, intermediate mesoderm (IM) at ~E8.5. C, formation of nephric duct (ND) primordium and nephrogenic cord (NC). D, ND elongation. E-F, epithelialization of ND, and formation of MM. G, formation of pseudostratified epithelium in caudal ND, while rostral ND remains cuboidal epithelium. H, outgrowth of UB. I, initial branching of UB within MM. J, UB after 3-4 rounds of branching. K, highly branched UB. L, elongation of collecting ducts to form the medulla. M, further CD elongation to form the papilla.

Figure 2. Genetic networks controlling nephric duct development, ureteric bud branching and nephron segmentation

A, genetic network controlling nephric duct development. See text for details. Dashed arrows indicate effects that occur only at some stages of development.B, genetic network downstream of RTKs that controls ureteric bud branching. See text for details. Bold arrows indicate major effects; dotted arrows, relationships that are uncertain. Modified from (Lu and al., 2009). C, genetic network involved in segmenting the nephron. See text for details. Pax2, Lhx1, and Brn1 are involved in establishing the distal segment; Notch2 (with some contribution from Notch1) is required to fix proximal identities and to establish proximal tubule precursors. PCT, proximal convoluted tubule. Diagram at bottom left indicates the color code used in B and C.

Figure 3. Cellular mechanisms of nephric duct/ureteric bud/collecting duct morphogenesis

A, ND cell movements during formation of the first UB tip domain. Cells in the ND with higher Ret signaling activity (blue) preferentially move (yellow arrows) to the dorsal ND, adjacent to the MM (pink oval), then form the first UB tip as it emerges. Cells with lower Ret activity (green) trail behind (red arrows) and populate the UB trunk. B, bipotential nature of UB tip cells. UB tips are shown in blue and trunks in yellow. Cells initially in the UB tip (colored red) divide and give rise to new tip cells (red) as well as cells that are left in the growing trunk (green). C, during lateral branching, or branching induced by transplanted MM (pink), tip cells (blue) are regenerated from trunk cells (yellow). D, Left: in late fetal and postnatal CDs, mitoses are preferentially oriented along the long axis of the duct, leading to duct elongation. Right: in several mutants, mitotic orientation is randomized, leading to increased diameter (and cyst formation) rather than elongation. E, most CD cells are elongated along the axis orthogonal to the CD long axis, suggesting that they undergo convergent extension movements leading to duct elongation. In Wnt9b mutants, however, cell orientation is altered, suggesting a defect in CE movements. Diagrams adapted from (Chi et al., 2009) (A), (Shakya et al., 2005) (B), (Karner et al., 2006) (D), (Karner et al., 2009) (E).

Figure 4. Molecules involved in maintaining the nephron progenitor pool, inducing and polarizing the nephron

(A). The MM contains at least two populations of progenitors, the capping mesenchyme (CM; in which the cells express Six2 and Cited1 and are resistant to Wnt9b) and induced mesenchyme (in which the cells lose Cited1 and begin to respond to Wnt 9b by expressing Lef1 and Wnt4). After MET, the nascent epithelial renal vesicles (RV) form a proximo-distal axis where the surface facing the cortex is distal (blue) and the medullary surface is proximal (red). Note that this axis appears inverted relative to the UB axis: the RV distal end is near to the UB proximal tip (P), the UB distal end is the ureter. (B) However, the distal cells of the comma-shaped body (CB) invade the proximal tip of the UB and fuse to form one continuous P/D axis (dashed gray arrow). (C) The proximal segment of the S-shaped body (SB) is thought to give rise to the future glomerulus and proximal tubule. (D)The mature nephron is further subdivided to glomerulus (G), proximal convoluted tubule (PCT), the straight segment of the proximal tubule (PST or S3), the loop of Henle with a descending thin limb (DTL) and ascending thin limb (ATL). The thick ascending limb (TAL) connects to the distal convoluted tubule (DCT), which connects to the collecting duct via a short connecting tubule (CNT). The identity of molecules and processes involved in subdividing the nephron is not yet known. Maintenance of progenitors and RV polarization: (E) Loss of Six2 leads to premature differentiation of renal epithelia, indicating that Six2 acts to antagonize the Wnt9b signal within the MM (A). (F) The Lhx1 gene is required to secure the distal identity of the CB; in its absence, the remaining cells will acquire the most proximal fate of the Bowman’s capsule. (G) Notch2 is required for maintaining the proximal identities (in its absence, the remaining cells acquire a distal identity and fuse with the UB). (H) Constitutive activation of Notch1 (which makes a small contribution to maintaining proximal fates) converts the entire MM into loosely organized cluster of proximal tubule-like epithelia lacking polarity (compare E with H), suggesting that Notch activity can suppress both the distal most and proximal most (podocyte, Bowman’s capsule) nephron fates and either augment the Wnt signal or act independent of it to induce the epithelialization of the entire MM. Diagrams adapted from (Kopan et al., 2007).