The kidneys play a critical homeostatic role in the regulation of body fluid composition and excretion of waste products. Here I review our understanding of how the three different vertebrate kidney types (pronephros, mesonephros, and metanephros) arise during mouse development with a more comprehensive focus on the molecular regulation of metanephros formation. A detailed understanding of the genetic hierarchies governing renal development will provide insights into the pathogenesis of kidney disorders, advance efforts to direct pluripotent stem cells into therapeutically useful renal lineages in vitro, and further our understanding of renal regenerative pathways that occur in vivo.

Overview of kidney structure and embryonic development

The kidneys are bilateral organs that regulate the composition and volume of the body fluids, and eliminate metabolic waste products. The filtering unit of the kidney is the nephron, which has a characteristic segmental organization. The glomerulus at the proximal end of the nephron filters the blood and passes the filtrate to a tubular epithelium that modifies it before delivering the urine to the collecting duct for disposal (see Figure 1). Mammalian renal development differs from that of most other organs in that it proceeds through a series of three successive phases, each marked by the formation of a more complex pair of kidneys. These kidneys, which are called the pronephros, mesonephros, and metanephros, develop in a cranial (anterior)-to-caudal (posterior) progression from stripes of mesodermal cells, called the intermediate mesoderm, that extend from the heart region to the tailbud of the embryo (see Figure 2). In amniotes (birds, mammals, and reptiles) the pronephros and the mesonephros are generally transient embryonic kidneys that subsequently degenerate and have little or no functionality. The metanephros, which persists as the definitive adult kidney, is characterized by an extensively branched collecting duct system and a large number of nephrons (∼11,000 in the mouse and 300,000–1 million in humans (Nyengaard and Bendtsen, 1992; Yuan et al., 2002). Structurally, the mammalian metanephros comprises an inner medullary region (containing collecting ducts and long loops of Henle—the nephron segment involved in urine concentration), an outer medullary region (containing short Loops of Henle and collecting ducts), and a cortical region (containing all other domains of the nephron; Figure 1). This gross structure is important for the functionality of the metanephric kidney as it establishes an osmotic gradient between the cortex and medulla that drives the extraction of water from the urine (Fenton and Knepper, 2007).

Figure 1

Structure of the mammalian kidney. Each kidney is comprised of a fibrous outer layer called the renal capsule, a peripheral layer called the cortex, and an inner layer called the medulla. The medulla is arranged in multiple pyramidal structures that together (more...)

Figure 2

Location of the intermediate mesoderm/nephrogenic cord. Schematic representation of a mouse embryo at E9.5 (left) and a cross-section through the trunk (right) showing the position of the intermediate mesoderm/nephrogenic cord.

Mouse kidney development begins with the formation of the pronephric duct (also known as the nephric or Wolffian duct; Figure 3). The nephric duct arises from the cranial portion of the intermediate mesoderm and grows caudally down the trunk to fuse with the urogenital sinus (ventral portion of the cloaca) at E11 (Hoar, 1976). As it migrates, the nephric duct induces the formation of mesonephric nephrons from the adjacent intermediate mesoderm (known as the nephrogenic cord or nephrogenic mesenchyme). Metanephros development is initiated at E10.5 at the caudal end of the nephric duct level with the hindlimb (27–28^th somite). Glial-derived growth factor (GDNF), secreted from a unique population of nephrogenic cells called the metanephric mesenchyme, induces an outgrowth from the nephric duct called the ureteric bud (UB) that then invades the metanephric mesenchyme (see Figure 3). The UB forms a T-shaped bifurcation at E11.5, and then undergoes ∼11 cycles of branching and elongation to generate the metanephric collecting duct system (Cebrian et al., 2004). During this process, each UB tip is surrounded by a cap of metanephric mesenchyme, a subset of which give rise to nephron progenitors that proliferate, differentiate into glomerular and tubular epithelial cells, and fuse with the collecting duct. Early studies demonstrated that reciprocal and inductive signaling between the UB and the metanephric mesenchyme are essential for initiating and maintaining the cycles of UB branching and nephron induction that underlie the formation of the metanephros (Grobstein, 1955; Grobstein, 1956).

Figure 3

Overview of kidney development. Mouse kidney development begins at E8.5 with the formation of the nephric duct primordium (blue) from the nephrogenic cord (yellow). Rostral nephric duct precursors are lost by apoptosis while caudal cells persist and grow (more...)

Structure and function of the nephron

The glomerulus is the most proximal component of the nephron and comprises a capillary tuft surrounded by highly specialized epithelial cells called podocytes (Quaggin and Kreidberg, 2008). Podocytes have a unique morphology that is characterized by several large primary projections, each of which is branched into smaller secondary extensions that branch again into a ‘comb-like’ array of ‘foot processes’. The foot processes from neighboring podocytes interdigitate, generating a series of narrow slits that are bridged by the slit diaphragm—a ‘protein zipper’ created by interactions between integral membrane proteins originating from adjacent foot processes. The foot processes are anchored to a specialized basal lamina, called the glomerular basement membrane (GBM), which also serves to separate the podocytes from the underlying endothelium. The endothelial cells of the glomerular capillary tuft are fenestrated, thus providing plasma solutes access to the GBM and slit diaphragm. Together, the fenestrated endothelium, GBM, and slit-diaphrgam make up the glomerular filter and function to retain high molecular weight proteins and blood cells in the circulation while allowing small molecules such as water, sugars, and electrolytes to enter the nephron (Quaggin and Kreidberg, 2008).

Once the filtrate has passed through the glomerular filter it encounters the first (proximal) portion of the tubule (see Figure 1). The proximal tubule is responsible for reabsorbing the majority of the filtrate, as it comprises metabolically useful solutes (Ullrich et al., 1963). The intermediate and the distal segments of the tubule further fine-tune the composition of the filtrate and play an important role in regulating potassium, calcium, and magnesium homeostasis, as well as water absorption. To achieve these functions, each segment of the tubule has a distinct cellular morphology and expresses unique sets of solute transporters. Finally, the modified filtrate flows into the collecting duct, which in the case of the metanephric kidney, acts as the final regulator of electrolyte balance and water absorption (Hebert et al., 2001).

The intermediate mesoderm

The mesoderm, together with the other two embryonic germ layers (ectoderm and endoderm), form during gastrulation. In general, gastrulation is characterized by the movement of an initially multi-potent population of epiblast cells into the interior of the embryo. In mammals, this occurs via the primitive streak, a furrow at the future caudal (posterior) end of the embryo where migrating epiblast cells undergo ingression (Gilbert, 2006). Once these cells have traversed the primitive streak they adopt either a mesodermal or endodermal fate and then become restricted to specific cell types within these lineages. This ‘patterning’ is best understood in fish and amphibian embryos, where signaling centers on opposite sides of the embryo (dorsal and ventral poles) release secreted factors, such as signaling molecules like the Bone Morphogenetic Proteins (BMPs) and their antagonists (reviewed by (De Robertis and Kuroda, 2004). It is hypothesized that ‘dorsal versus ventral’ interactions, as well as positive and negative feedback loops occurring within each signaling center, establish morphogenic gradients across the gastrulating embryo. Particular mesodermal cell fates are thought to be induced, or ‘specified’, in response to high, medium, or low concentrations of these morphogens. Ultimately, dorsal-ventral patterning results in the mesoderm being subdivided into at least four major populations: (1) notochord (a transient ‘embryonic backbone’), (2) paraxial mesoderm (future somites ie progenitors of certain muscles and other connective tissues), (3) intermediate mesoderm (the precursor to the kidneys), and (4) lateral plate mesoderm (includes progenitors of the heart, blood, and vascular cells (see Figure 2).

Perturbations in dorsal or ventral signaling pathways alter the proportions of these mesodermal populations within the embryo. ‘Dorsalized’ embryos have expanded notochord and paraxial mesoderm at the expense of intermediate and lateral plate mesoderm. Whereas ‘ventralized’ embryos have increased lateral plate and intermediate mesoderm at the expense of paraxial mesoderm and notochord. BMPs are potent ventralizing factors and there is considerable evidence from studies in Xenopus, zebrafish, and chicken to indicate that BMPs act during gastrulation to determine the size and location of the intermediate mesoderm along the medial-lateral axis of the embryo (James and Schultheiss, 2005; Kishimoto et al., 1997; Neave et al., 1997; Nguyen et al., 1998; Xu et al., 1999). BMPs are also needed after gastrulation to induce/maintain the expression of early acting pro-renal genes in the pronephros and to regulate various aspects of metanephric development (Bracken et al., 2008; Obara-Ishihara et al., 1999).

The pronephros and formation of the nephric duct

The mouse pronephros arises from the portion of the intermediate mesoderm that is level with presumptive somites 5–8 at E8.0 (Bouchard et al., 2000; Vetter and Gibley, 1966). In this region, precursors of the pronephric duct separate away from the intermediate mesoderm and form a short longitudinal rod of cells that then grows caudally. These cells undergo a mesenchymal-to-epithelial transition and form the epithelial tube of the pronephric duct (also known as the nephric duct). At the same time, ∼3 small condensations of mesenchymal cells that may represent pronephric nephron precursors arise from the nephrogenic cord. However, these clusters do not differentiate further and pronephros development is aborted (Vetter and Gibley, 1966). The nephric duct degenerates by apoptosis soon after forming but persists in more caudal positions of the trunk where it is required for the formation of the mesonephric and metanephric kidneys (Pietila and Vainio, 2005; Pole et al., 2002).

The Mesonephros

The mouse mesonephros consists of up to ∼18 pairs of tubules that extend from the level of somite 10 to 17 and are divided into distinct cranial and caudal sets (Sainio, 2003; Vetter and Gibley, 1966). The nephrons of the cranial set develop rudimentary glomeruli, are frequently branched, and join with the nephric duct at 4–6 sites. Based on the observation that the cranial nephrons appear to be in continuous contact with the nephric duct during their development it has been suggested that the cranial set may form directly from the nephric duct, perhaps as outgrowths (Sainio et al., 1997). However, data from chicken and mouse studies indicate that the duct only contributes cells to a short connecting segment (Brenner-Anantharam et al., 2007; Croisille et al., 1976; Mugford et al., 2008). In contrast, the caudal pairs, which make up the bulk of the mesonephros, are comprised of primitive unbranched tubules that do not connect to the nephric duct and derive from the nephrogenic cord (see Figure 2). These tubules first appear as condensations of nephrogenic cord cells level with somites 8–9 at E9.0 (Vetter and Gibley, 1966). These cells undergo a mesenchymal-to-epithelial transition, initially forming a ‘renal vesicle’ and then elongating into a ‘S-shaped body’ (Smith and Mackay, 1991). The mesonephros begins degenerating at E14.5 and within 24 hours almost all of the tubules undergo apoptosis and disappear in a caudal to cranial direction (Sainio et al., 1997; Smith and Mackay, 1991). In females, all of the tubules are lost, whereas in males some of the cranial tubules remain intact, contributing to the epididymal ducts of the testis (Vetter and Gibley, 1966).

The molecular regulation of mouse mesonephros development has received little attention, presumably because of the limited functionality and transient existence of the organ. Classical experiments in chick embryos have demonstrated that microsurgical disruption of nephric duct extension results in a failure of mesonephric nephron formation in the adjacent nephrogenic cord (Boyden, 1927; Waddington, 1938). Thus, it has long been suspected that nephron-inducing signals emanate from the nephric duct as it migrates to the cloaca, resulting in the formation of mesonephric nephrons in a craniocaudal sequence. The gene responsible for nephron induction was recently identified as Wnt9b, encoding a member of the Wnt family of secreted signaling molecules that is expressed by the nephric duct during mouse mesonephric and metanephric development (Carroll et al., 2005). Wnt9b mutants also lack metanephric nephrons (see below), suggesting that similar nephron-inducing programs underlie nephron formation in both mesonephric and metanephric kidneys. In support of this, the transcription factors Pax2, Wilms’ tumor suppressor1 (Wt1), Foxc1, and Six1, which are involved in metanephros formation (see below), are also involved in mesonephric nephron formation (Note: Wt1 and Six1 are reported to be only required for the formation of the caudal set of nephrons, however the cranial tubules seen in these mutants may actually represent arrested nephric duct outgrowths; (Kobayashi et al., 2007; Mugford et al., 2008; Sainio et al., 1997; Torres et al., 1995).

The Metanephros

Our understanding of the developmental pathways underlying metanephros formation has advanced significantly over the last two decades. The metanephric mesenchyme expresses a large number of regulatory genes, including the transcriptional regulators Pax2, Wt1, Eya1, Six1, Six2, Osr1, and Hox11. These factors function as regulators of the formation, proliferation, and survival of the metanephric mesenchyme and/or as upstream activators of Gdnf.

Specification of the metanephric mesenchyme

The nephric duct is not required for the initial specification of the metanephric mesenchyme as in the Gata3 knockout mouse, Pax2-expressing metanephric mesenchyme is still found despite failure of the nephric duct to migrate to this region of the embryo (Grote et al., 2006). Early key factors that have been identified as being necessary for the formation of a morphologically distinct region of metanephric mesenchyme are the transcriptional regulators Eya1, Six1/Six4, and Odd1.

Eyes-absent-1 (Eya) and Sine-Oculis (Six)

Eya1, a homolog of Drosophila eyes absent, encodes a transcriptional co-activator that can complex with other transcription factors to induce the expression of target genes (Jemc and Rebay, 2007). At E8.5, Eya1 is expressed in the nephrogenic cord caudal to the mesonephros but gets progressively restricted until it is only expressed by the metanephric mesenchyme at E11.5 (Sajithlal et al., 2005). Eya1-deficient embryos do not form a morphologically distinct population of metanephric mesenchyme or a UB at E10.5 (Xu et al., 1999). Eya1 null embryos display an early loss of Gdnf expression in the nephrogenic cord (from E9.5 onwards). This defect is not caused by a failure in the formation of the intermediate mesoderm, as normal expression of Wt1 and Pax2 is observed in the nephrogenic cord at E9.5 (Sajithlal et al., 2005; Xu et al., 1999). At E10.5, transcripts for Pax2 and Six2 are absent in the metanephric region of Eya1 null embryos, suggesting that the metanephric mesenchyme fails to be specified in the mutants. In addition, significant apoptosis in the metanephric region is also observed in the mutants at this stage (Sajithlal et al., 2005; Xu et al., 1999). Although an absence of metanephric mesenchyme marker expression could be secondary to cell loss, a more recent analysis of Eya1 hypomorphic mutants has provided further evidence to support an early role for Eya1 during metanephric mesenchyme differentiation. Eya1 hypomorphs with ∼20% of normal Eya1 protein levels initially develop both the metanephric mesenchyme and a UB, although further UB outgrowth and branching is defective (Sajithlal et al., 2005). Expression of Pax2, Six1, and Gdnf in the metanephric mesenchyme is reduced in the hypomorphs at E10.5, suggesting that Eya1 is required to induce or maintain the expression of these genes. Taken together, these results suggest that Eya1 acts during the early stages of metanephric kidney development to convert nephrogenic cord cells into metanephric mesenchyme, at least in part, by regulating the expression of Pax2, Six1, Six2, and Gdnf.

Eya1 has no apparent DNA-binding activity and is translocated from the cytoplasm to the nucleus by binding to the Six (sine oculis) homeobox transcription factors (Ohto et al., 1999). Candidate Six proteins involved in renal development include Six1, Six2, and Six4, which show overlapping expression patterns in the nephrogenic cord and metanephric mesenchyme (Kobayashi et al., 2007; Li et al., 2003; Oliver et al., 1995; Xu et al., 2003). Functionally, the Six proteins may share similar or redundant activities. Consistent with this, no single knock-out of a Six gene recapitulates the severity of the Eya1 null phenotype. In Six1 null embryos, the metanephric mesenchyme is specified, as determined by morphology and the expression of Wt1 and Eya1, but its size is reduced (Li et al., 2003). Expression of the metanephric mesenchyme markers Sall1, Pax2, and Six2 are severely reduced in the mutants, although differing degrees of down-regulation have been reported (Kobayashi et al., 2007; Li et al., 2003; Sajithlal et al., 2005; Xu et al., 2003). Gdnf is normally expressed in the metanephric mesenchyme of Six1 mutants, although its overall expression domain is smaller given the reduced size of the metanephric mesenchyme (Xu et al., 2003). The UB initially forms at E10.5 in Six1 mutants but often fails to invade the metanephric mesenchyme, perhaps due to a reduced local concentration of Gdnf caused by the smaller mass of metanephric mesenchyme (Yu et al., 2004). As a result, apoptosis of the metanephric mesenchyme ensues at E11.5 and renal agenesis is seen in the majority of Six1-null newborns (Kobayashi et al., 2007; Xu et al., 2003).

Six2 null embryos do not show defects in the initial specification of the metanephric mesenchyme or UB outgrowth, despite expression of Six2 in the metanephric mesenchyme at E10 and the finding that Six2 can activate Gdnf expression (Brodbeck et al., 2004; Self et al., 2006). However, later abnormalities in early nephron formation are found at E11.5 (see below). Six1/Six2 double mutants have not yet been reported. Six4-deficient mice are viable and fertile and exhibit no major developmental defects (Ozaki et al., 2001). A recent analysis of Six1/Six4-deficient embryos has demonstrated clear functional redundancy between the Six1 and Six4 proteins with loss of both genes leading to a more severe metanephric phenotype than that of Six1-deficient mutants (Kobayashi et al., 2007). A morphologically distinct region of metanephric mesenchyme is missing in Six1/Six4 double mutants and there is an absence of Pax2, Sall1, and Gdnf expression in the metanephric region. In addition, Pax8, which functions redundantly with Pax2 (see above), is transiently expressed in the metanephric mesenchyme at E10.0 and while it is normally expressed in Six1-deficient embryos, it is absent in the Six1/Six4 double mutants. Nephrogenic cells appear to still be present in the Six1/Six4 mutants based on the expression of Wt1, Six1, and Osr1 (Kobayashi et al., 2007). No apoptosis in the metanephric region was observed at E10.5, although it presumably occurs at least as early as E11.5 based on the Six1 phenotype (see above). The UB fails to form in Six1/Six4 mutants and renal agenesis is seen in all of the newborns.

Overall, the phenotype of Six1/Six4 mutants is similar to that of Eya1 mutants, strongly suggesting that Six1 and Six4 interact redundantly with Eya1 to activate expression of metanephric regulators such as Pax2/8, Six2, Sall1, and Gdnf. Whether Eya1/Six complexes directly activate the expression of these genes is not clear, although chromatin immunoprecipitation experiments have shown that Eya1 and Six1 are present on Gdnf regulatory sequences (Li et al., 2003).

Eya1 can interact with other transcription factors and a recent study has implicated an Eya1-Pax2-Hox11 complex as a direct activator of Six2 as well as Gdnf (Gong et al., 2007; Mugford et al., 2008). Consistent with this, targeted inactivation of all three Hox11 paralogs causes a significant reduction in Six2 and Gdnf expression in the metanephric mesenchyme at E10.5 (Wellik et al., 2002). However, expression of Pax2 is normal in Hox11 triple mutants whereas it is absent in Six1/Six4 double mutants, suggesting that a Hox11-Eya1-Pax2 complex may act later in development, perhaps after an Eya1/Six1/4 complex has upregulated Pax2 and Sall1 in the metanephric mesenchyme (see Figure 4). The ability of Eya1 to interact in multiple complexes and to induce the expression of genes encoding transcription factors it physically associates with, make it difficult to place Eya1 in a simple linear pathway.

Figure 4

A model of potential epistatic interactions occurring between early-acting transcription factors in the nephrogenic cord at the level of the presumptive metanephros.

Odd-skipped related-1

Odd-skipped related-1 (Odd1) encodes a zinc-finger transcription factor related to the Drosophila pair rule gene odd skipped (Coulter et al., 1990). Odd1 is one of the earliest molecular markers of the intermediate mesoderm in the mouse embryo and is first activated in these cells shortly after they migrate from the primitive streak at the midgastrula stage (Wang et al., 2005). At E8.5–9.5, Odd1 transcripts are found throughout the intermediate mesoderm/nephrogenic cord and in the metanephric mesenchyme but not the UB at E10.5 (James et al., 2006; So and Danielian, 1999; Wang et al., 2005). In Odd1 null embryos, neither the UB nor a morphologically distinct population of metanephric mesenchyme can be detected and renal agenesis occurs in mutants that survive to late gestation (Wang et al., 2005). Consistent with this, Odd1 mutants completely lack Eya1 and Pax2 in the metanephric region at E9.5 (James et al., 2006). Wt1 expression levels are reduced in the Odd1 mutants, but Wt1 protein can still be detected in the metanephric region. High levels of apoptosis are evident in the mutant metanephric mesenchyme at E10.5, consistent with the downregulation of Eya1 (see above; James et al., 2006; Wang et al., 2005). At E11.5, transcripts for Six2, Gdnf, and Sall1 cannot be detected, also possibly due to the absence of Eya1, however cell loss by apoptosis may contribute to the failure to detect markers of the metanephric mesenchyme.

Odd1 mutants also display nephric duct defects that are characterized by discontinuous expression of Ret, Lhx1, Pax2, posterior truncations, and a smaller nephric duct diameter (James et al., 2006; Wang et al., 2005). The cause of these abnormalities has not been examined but may be due to increased nephric duct cell death, perhaps indirectly resulting from the loss of the adjacent nephrogenic cord (given that Odd1 transcripts are not found in the migrating nephric duct; James et al., 2006). Interestingly, the duct defects are more severe on the left side of the embryo, suggesting that pathways that establish left-right patterning may interact with Odd1 (Wang et al., 2005).

The direct targets of Odd1 during kidney development are not known and current evidence indicates that Odd family members act as transcriptional repressors (Goldstein et al., 2005; Tena et al., 2007). Thus, the effects of Odd1 on renal genes such as Eya1 and Pax2 may be mediated indirectly via the inhibition of a repressor of these genes. Taken together, these findings place Odd1 as one of the earliest acting genes involved in metanephros formation and suggest that Odd1 acts upstream Eya1, Pax2, and Wt1 in the nephrogenic cord to promote metanephric mesenchyme formation and survival (see Figure 4 and Figure 5).

Figure 5

Key molecular pathways involved in early metanephric kidney development. At E10.5, the metanephric mesenchyme (red) comprises a unique subpopulation of the nephrogenic cord (yellow). Expression of the Glial-derived neurotrophic factor (Gdnf) is resticted (more...)

Paired-box transcription factor (Pax) 2 and Pax8

Pax2 is expressed in the nephrogenic cord in the metanephric region at E9.5 and then in the metanephric mesenchyme at E10.0. Transcripts for Pax2 are also found in the nephric duct (as described above) and in the UB as it invades the metanephric mesenchyme (Brophy et al., 2001; Torres et al., 1995). In Pax2 mutants, the nephric duct does not reach the cloaca, expression of Ret is lost, and the duct starts degenerating by E12.5. As a result, the UB never forms and metanephric development does not occur (Torres et al., 1995). The metanephric mesenchyme can be morphologically distinguished in Pax2 mutants and expresses Eya1, Six1, Six2 (albeit weakly) and Sall1, indicating that Pax2 is not required for the initial specification of the metanephric mesenchyme from the nephrogenic cord (Torres et al., 1995; Xu et al., 2003). However, the transient expression of Pax8 in the metanephric mesenchyme at E10.0 may mask an earlier role for Pax2 and Pax8 in the formation of the metanephric mesenchyme (Kobayashi et al., 2007). Transcripts for Gdnf are reduced in the Pax2-deficient metanephric mesenchyme, consistent with Pax2 participating in a transcriptional complex with Eya1 and Hox11 proteins on Gdnf regulatory sequences (see above;(Sajithlal et al., 2005).

Metanephric nephron development

Nephron formation begins at E11.5 with the appearance of small clusters of mesenchymal cells on either side of the unbranched UB tip. These pre-tubular aggregates initially consist of 4–6 cells that are contiguous with the cap mesenchyme but undergo rapid proliferation to form a cluster of approximately 30 cells (Bard et al., 2001). Lineage labeling experiments both in vitro and in vivo have confirmed that the cap mesenchyme gives rise to all of the epithelial segments of the nephron (podocytes through to the distal tubule; Boyle et al., 2008; Herzlinger et al., 1992; Kobayashi et al., 2008; Osafune et al., 2006). Following UB branching and growth, the pre-tubular aggregates become located beneath the UB tips (known as the proximal side). Similar to the morphogenesis seen for mesonephric nephrons, the pre-tubular aggregates undergo a mesenchymal-to-epithelial transition to form renal vesicles at E12.5 and then proliferate to give rise to comma- and S-shaped bodies that fuse with the collecting duct epithelium (see Figure 6).

Figure 6

Metanephric nephron formation. Nephrons arise from pretubular aggregates, a subpopulation of the cap mesenchyme, in response to Wnt9b. Early molecular markers of pretubular aggregates are Pax8, Fgf8, and Wnt4. Wnt4 maintains the expression of these genes, (more...)

Based on restricted gene expression patterns, the S-shaped body can be subdivided into podocyte progenitors and the precursors of the proximal and distal tubule segments, although definitive lineage labeling experiments have not yet been done (Dressler, 2006). The cells that make up the cleft at the proximal end of the S-shaped body (farthest away from the collecting duct) express Wt1 and mature into podocytes. These cells also produce VEGF and attract angioblasts that contribute to the formation of the glomerulus (Eremina et al., 2003). As proliferation of the nascent nephron continues, the proximal and distal tubule segments become convoluted while the region between them grows down into the medullary zone to form the Loop of Henle (Neiss, 1982). Nephrons located in superficial or midcortical regions of the kidney possess short loops of Henle that turn within the cortex or outer medulla zone. More deeply located nephrons (juxtamedullary nephrons) have long loops of Henle that descend into the inner medulla region (Hebert et al., 2001). In addition to the loop of Henle, metanephric nephrons are also distinguished from other nephron types by the macula densa, a population of salt- and fluid-sensing cells in the lining of the distal tubule (see Figure 1). These cells make contact with the parent glomerulus of the nephron and form part of a tubuloglomerular feedback system that couples distal nephron flow with glomerular filtration rate and ensures that the flow through the nephron is tightly controlled (Castrop, 2007).

Concluding remarks

Kidney development in amniotes is unique with respect to the other organs in that three separate kidney types arise during embryogenesis. From an evolutionary perspective, the acquisition of additional kidney structures is thought to have occurred during the transition of a freshwater protovertebrate to a dry terrestrial environment (Smith, 1959). The pronephric kidney in lower vertebrates with freshwater larvae, such as Xenopus and zebrafish, plays a critical role in water excretion and prevents the embryo from dying an early death by edema. As the animal grows, additional renal function is necessary in order to cope with the added demands on waste excretion and fluid homeostasis. Therefore, the mesonephric kidney may have evolved in response to greater body mass and associated factors such as increased blood pressure (Vize et al., 1997). The metanephric kidney, with its unique water conserving ability, was the adaptation that allowed amniotes to live and breed on dry land.

In mammals, the embryo is protected from osmotic challenges coming from the external environment by virtue of in utero development, while the problem of waste excretion is ameliorated by the allantois and placenta. Thus, the mammalian embryo has a reduced requirement for the pronephric and mesonephric kidneys and in the case of the mouse these have regressed to rudimentary structures that are short-lived. The (pro)nephric duct has been retained, as the metanephric kidney is dependent upon it as the source of the ureteric epithelium, while some of the mesonephric tubules are co-opted in males for the epididymal ducts of the testis.

Each kidney type is comprised of similar cell types and performs common renal functions. It is not surprising then, that the genes involved in the formation of one kidney type are re-employed in the others. This means that the study of gene function in one kidney type, such as the use of Xenopus and Zebrafish to examine genetic hierarchies involved in pronephros development, is likely to yield information that is useful to all kidney types. Ultimately however, a detailed understanding of metanephric kidney development can only come from the study of these genes in mammals. In the past, analyzing the function of murine genes central to the development of all kidney types was hampered by early nephric duct defects preventing an assessment of gene function in the metanephros. This has now been largely overcome by employing Cre-Lox technology and the generation of nephric duct- and metanephric mesenchyme-restricted Cre recombinase lines. As additional lines are made, it should be possible to inactivate genes in smaller, lineage-restricted populations of cells, thus providing the level of precision and temporal control needed to unravel the complex epistatic relationships currently hindering the field. A number of renal genes have been implicated in human disease, including PAX2 (renal-coloboma syndrome), WT1 (Wilms’ tumor and urogenital disorders), SIX1 and EYA1 (branchio-oto-renal syndrome), GATA3 (HDR syndrome), and SALL1 (Townes-Brocks syndrome; (Dressler, 2006). Thus, a greater understanding of their role during metanephric kidney development will provide a molecular basis for the pathogenesis of these diseases and may lead to new therapeutic or preventative treatments.

Knowledge of embryonic kidney development will also form the foundation for developing stem cell-based strategies to treat renal disease. Some of these approaches are based on the directed differentiation of embryonic stem (ES) or other multipotent cells into kidney cells using cocktails of growth factors followed by transplantation into embryonic or adult kidneys (Bruce et al., 2007; Kim and Dressler, 2005; Kobayashi et al., 2005; Schuldiner et al., 2000; Vigneau et al., 2007). At present, this approach has yielded limited success but will likely improve with a better understanding of the genetic hierarchies governing the formation of the different kidney types. For example, in order to make metanephric mesenchyme from pluripotent stem cells it may be necessary to first convert these cells into Pax2/8⁺ and Odd1⁺ intermediate mesoderm and then direct them into a metanephric mesenchyme fate by inducing factors such Eya1, Six2, and Hox11. Recent studies in vivo have shown that ectopic expression of Hox11 in cranial portions of the nephrogenic cord, where it is not normally expressed, is sufficient to induce Six2 expression and transform mesonephric nephrons into more metanephric-like nephrons (Mugford et al., 2008). Thus, the activation of single regulatory factors in stem cell-derived intermediate mesoderm may be sufficient to initiate metanephric mesenchyme formation in vitro. It is unreasonable to hope for the generation of a complete kidney in vitro, however specific cell types, such as the cap mesenchyme, may have therapeutic potential. In the mouse, the cap mesenchyme is lost at postnatal day 3 and nephrogenesis ceases abruptly. In contrast, the UB still expresses Wnt9b at this time and retains the ability to induce nephrons and promote embryonic metanephric mesenchyme survival in vitro (Hartman et al., 2007). Although it is not known how long the nephron-inducing activity of the postnatal UB lasts, it raises the possibility that the transplantation of ES-cell derived cap mesenchyme into newborn or adult kidneys could lead to a restoration of nephrogenesis and a potential therapy for renal defects and disease.

The ability to differentiate pluripotent stem cells into renal cells in vitro will also be useful for studying kidney disease in humans. The recent discovery that somatic cells can be converted into ES-like cells, called induced pluripotent stem cells (iPS) now makes it relatively easy to create a multitude of disease-specific iPS lines (Park et al., 2008; Yamanaka, 2008). Being able to create specific renal cell lineages, such as proximal and distal tubular epithelial cells and podocytes, from patients with renal disorders will provide valuable in vitro tools to dissect the pathogenesis of diseases such as glomerulopathies and polycystic kidney disease.

One of the limitations of using pluripotent stem cell-derived tissues for cell-based therapies is the risk of teratoma formation (Little, 2006). Hence, there is an ongoing search for a resident renal stem cell that would comprise a more therapeutically tractable population to target. The mammalian kidney is known to possess a limited ability to repair the tubular epithelium of damaged nephrons (Humphreys and Bonventre, 2007). Whether this repair is mediated by the dedifferentiation and proliferation of surviving epithelial cells or whether a resident renal stem cell is involved has become the subject of recent investigation. Although candidate renal stem cells have been found in the renal papilla, tubular epithelium, and the urinary pole of the glomerulus, in vivo genetic lineage-labeling and serial transplantation experiments are needed in order to confirm their stem cell properties (Gupta et al., 2006; Lazzeri et al., 2007; Maeshima, 2007; Maeshima et al., 2006; Oliver et al., 2004; Sagrinati et al., 2006). A recent fate-mapping analysis of ischemia-reperfusion injured kidneys showed that surviving tubular epithelial cells are the predominant source of the regenerated tissue (Humphreys et al., 2008). While this experiment rules out an extra-tubular source of renal stem cells, it does not exclude the possibility that a resident epithelial progenitor/stem cell is responsible for the repair. Alternatively, each epithelial cell in the nephron may possess an inherent ability to dedifferentiate, proliferate, and re-differentiate into an epithelial cell following damage. There is some evidence to suggest that re-differentiating epithelial cells express embryonic renal genes such as Pax2 (Villanueva et al., 2006). This suggests that tubular regeneration may recapitulate aspects of renal development. If so, then the study of embryonic kidney development may provide insights into the mechanism of renal repair following acute kidney injury.

In summary, elucidating the molecular basis of kidney development will increase our understanding of renal birth defects and disease, provide a foundation for directing the differentiation of pluripotent stem cells into clinically useful renal cells, and further our knowledge of epithelial repair following kidney injury. While there is still much to be learnt in each of these arenas, there is clearly much to be gained.

Acknowledgments

I wish to thank Joseph Bonventre, Jordan Kreidberg, and Andrew McMahon, as well as the members of their laboratories and my own for their support, collaborations, and valuable discussions. This work is supported in part from grants from the Harvard Stem Cell Institute and the NIH (DK077186–01A1).

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Edited by Kenneth R. Chien. Last revised September 5, 2008. Published January 15, 2009. This chapter should be cited as: Davidson, A.J., Mouse kidney development (January 15, 2009), StemBook, ed. The Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.34.1, http://www.stembook.org.