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Development of Murine Urinary System | ATLAS-D2K Center

Development of Murine Urinary System

Provided by Matt Kaufman, University of Edinburgh. Other contributors are Jamie Davies, Peter Koopman, Melissa Little, Cathy Mendelsohn, Gen Yamada and Andrew McMahon.
2010 (GUDMAP)

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A note about staging

The definitions of Theiler stages used in this essay, and their relationship to days post-coitum (dpc), are those that appear on the EMAP website (no longer active, but you can find the paper here).

In this document, each Theiler stage is identified with one 'average' age, and a range of variation of real ages, centring on this average, that can be seen when real developing embryos are studied. These appear below. For simplicity, the rest of this essay quotes only the average age.

Theiler Stage (TS) Alternative Staging
TS10 7 dpc (range 6.5 - 7.75)
TS11 7.5 dpc (range 7.25 - 8)
TS12 8 dpc (range 7.5 - 8.75
TS13 8.5 dpc (range 8 - 9.25)
TS14 9 dpc (range 8.5 - 9.75)
TS15 9.5 dpc (range 9 - 10.25)
TS16 10 dpc (range 9.5 - 10.75)
TS17 10.5 dpc (range 10 - 11.25)
TS18 11 dpc (range 10.5 - 11.25)
TS19 11.5 dpc (range 11.5 - 12.25)
TS20 12 dpc (range 11.5 - 13)
TS21 13 dpc (range 12.5 - 14)
TS22 14 dpc (range 13.5 - 15)
TS23 15 dpc
TS24 16 dpc
TS25 17 dpc
TS26 18 dpc
TS27 P0 - P3
TS28 P4 - Adult

P = postnatal days

Mouse developmental stages
Diagrammatic representations of the developing mouse at stages TS19 - 11.5dpc, TS20 - 12dpc, TS23 - 15dpc and TS28 - Adult.

The development of the murine kidneys

As noted above, the metanephros develops from the most caudal part of the nephrogenic cord that is itself derived from the intermediate plate mesoderm (see above). The initial renal anlage that develops from the most rostral part of the nephrogenic cord is termed the pronephros. The latter is not believed to function in the mouse, or in any other mammal. However, within the pronephros, a relatively small number of pronephric (or nephrotomal) vesicles form in a cranio-caudal direction, and these “drain” into the pronephric duct. As the pronephros is a relatively transient structure in mammals, the absence of differentiated glomeruli within it strongly suggests that it probably does not act as even a primitive excretory organ. Despite the complete degeneration of the pronephros, the pronephric duct is retained. This structure is then taken over by the mesonephros (also termed the “Wolffian” body), and is only then termed the mesonephric portion of the nephric duct.

The early urogenital system at TS17 (10.5 dpc)
The early urogenital system at TS17 (10.5 dpc).
Schematic diagrams show the 3-dimensional anatomy of the urogenital system at the caudal end of the mouse embryo. Dorsal (D), ventral (V) and anterior (A), posterior (P) orientations are indicated. The hind limb buds are visible. A lateral view of one half of the urogenital system (left) and a ventral view of the entire urogenital system (right) are shown. The gonad (go, dark grey) lies medial to the mesonephros (mes, light grey). Primordial germ cells (white spheres) are part of the gonad. Cranial and caudal mesonephric tubules (mt, brown) develop within the mesonephros. Cranial tubules are connected to the nephric duct (nd, brown). The metanephric mesenchyme (mm, dark purple) lies posterior and dorsal to the mesonephros and will develop into the metanephros (kidney). The nephric duct lies ventral to the mesonephros and metanephric mesenchyme. At this stage, the ureteric bud has not yet emerged from the nephric duct, and the region of the nephric duct adjacent to the metanephric mesenchyme is called the nephric duct metanephric portion (nd-mm, brown). The cloaca lies posterior to the urogenital system (cl, blue). Diagram modified from: A high-resolution anatomical ontology of the developing murine genitourinary tract. M. H. Little et al. Gene Expression Patterns 7 (2007) 680–699.

By contrast to the pronephros, the histological features of the mesonephros, with its primitive glomeruli, suggest that it probably functions as a primitive kidney, and is involved in the production of much of the amniotic fluid. Within the two mesonephroi, one located on either side of the dorsal mesentery of the hindgut, a substantial number (in the region of about 40 or more) of cranio-caudally segmented mesonephric tubules are formed. It has, however, been suggested that only the most rostrally located 4-6 pairs of mesonephric tubules drain into the mesonephric portion of the nephric duct. This is now seen to extend along the length of the mesonephroi, being located towards their lateral sides. The mesonephros is also retained over a considerably longer period than the pronephros, but gradually undergoes regression in a cranio-caudal direction. While the rostral part displays clear evidence of regression its more caudal part appears to display evidence of functional activity. Within the medial part of the mesonephros, vesicles are formed, although no glomeruli are formed there in this species. It is, however, difficult to believe that the relatively enormous mesonephroi do not have an excretory role in the mouse, only serving as a base for gonadal differentiation. In the human embryo, the medial part of the mesonephric tubules enlarges, become invaginated by capillaries, and form glomeruli. These then take on an excretory role. In the mouse, the mesonephric ducts appear to be patent throughout their length.

During the period that the majority of the mesonephroi are present, they form two quite voluminous structures. These are located one on either side of the hindgut, and occupy a substantial part of the caudal half of the peritoneal cavity. It is largely due to their presence (and that of the liver and stomach with its associated gastric dilatation in the upper part of the peritoneal cavity, and the urogenital sinus in its lower part) that the potential space within the peritoneal cavity is so limited. This thus stimulates the extrusion of the embryonic midgut region into the so-called physiological umbilical hernia where the midgut can increase in length, and undergo the initial stages of its rotation, before it returns into the peritoneal cavity in order to complete its rotation and differentiation.

Similarly, during the period when the majority of the mesonephros is still present, the caudal part of the mesonephric duct extends caudally until it makes contact with the urogenital sinus in the region that eventually corresponds with the supero-lateral part of the trigone of the future bladder. It is also at about this stage that the urogenital sinus is separated from the caudal part of the hindgut due to the down growth of the urorectal septum. Once contact is made between the mesonephric portion of the nephric duct and the urogenital sinus, it appears likely that any excretory products produced by the mesonephros will be transferred into the urogenital sinus. Shortly after contact is established between the caudal part of the mesonephric duct and the urogenital sinus, this stimulates the formation of a cranio-laterally directed diverticulum, termed the ureteric bud. It is at this stage that the mesonephric tissue shows more rapid evidence of regression, and much of its rostral part has by this time completely regressed.

The two ureteric buds grow in the direction of the most caudal part of the nephrogenic cord tissue, and this is then stimulated (possibly by inductive interaction) to form the primitive metanephros. This will in due course develop into the definitive kidney, or metanephros.

Unlike the mesonephros, the metanephros shows no obvious evidence of cranio-caudal segmentation. The metanephros, in fact, has a rounded appearance, and the future glomeruli (one of the critical components of the excretory system) tend to be located towards its periphery. When the ureteric bud makes contact with the metanephric mesenchyme, the terminal parts of the ureteric buds start to bifurcate. Mesenchyme closely apposed to the tips of the buds is called cap mesenchyme; it will later go on to form nephrons.

Development of the metanephros - 3D
Development of the metanephros (kidney).
Schematic diagrams show 3-dimensional views of the urogenital system at TS19 (11.5 dpc) and views of the kidneys and ureters at TS20 (12 dpc) and TS21 (13 dpc). Anterior (A), posterior (P), ventral (V) and dorsal (D) orientations are indicated. At TS19, mesonephroi (mes, light grey), mesonephric tubules (mt, brown) and gonads (go, dark grey) located in the anterior urogenital system, will become parts of the adult reproductive system. At TS19, the paired nephric ducts (nd, brown) have extended down the embryo and connect to the urogenital sinus (ugs, blue), which develops from the anterior cloaca (cl, blue). The nephric duct segments, below the level of the ureteric bud (ub), are called the common nephric ducts (cnd). These connect the nephric ducts to the urogenital sinus. At this stage, dorsal to the developing gonads, the ureteric buds (ub) have emerged from the nephric ducts and are surrounded by metanephric mesenchyme (mm, purple). These two tissue types will give rise to the metanephros or kidney. At TS19, each of the two ureteric buds are comprised of a ureteric tip and stalk. The ureteric buds begin to branch and at TS20, the ureteric tree (or primitive collecting duct) is comprised of terminal ureteric tips (orange) and ureteric trunks (brown). The metanephric mesenchyme condenses around each tip forming a cap mesenchyme (dark purple). Throughout development, and until just after birth in the mouse, the ureteric tree will continue to branch and grow, with cap mesenchyme surrounding each ureteric tip. Also during development, whilst the ureteric tree continues to branch, cells of the cap mesenchyme undergo a mesenchymal to epithelial transition to form nephrons, via a process called nephrogenesis. Diagram modified from: An illustrated anatomical ontology of the developing mouse lower urogenital tract. Georgas et al.

The detailed events associated with the differentiation of the nephrogenic mesenchyme are somewhat complex. It has been suggested that each terminal branch of the ureteric bud, the ureteric tips, stimulate the associated cap mesenchyme tissue to form a renal vesicle (the most primitive stage of nephron development: a stage I nephron). This then elongates, becomes a comma-shaped and then an S-shaped body (stage II nephron), and makes contact with and fuses with the distal component of the ureteric bud, the ureteric tips. The ureteric tips and trunks (ureteric tree) then form the collecting duct. The proximal end of the S-shaped body gives rise to Bowman’s capsule (also termed the glomerular capsule) and glomerulus, whilst the medial and distal ends will become the nephron tubules. Endothelial cells invade the cleft in the S-shaped body to make a capillary knot-like outgrowth, the glomerular tuft, which goes on to form the glomerulus. The visceral epithelium, or podocyte layer because it consists of podocytes, of the renal corpuscle is closely apposed to the endothelial cells of the glomerulus. Together, the Bowman’s capsule and the glomerulus comprise the definitive renal corpuscle. The rest of the nephron elongates to form components of the proximal tubule, the loop of Henle, the distal tubule and connecting tubule segments. The distal pole of the developing nephron connects to the ureteric tip that induced it at an early stage of nephron/ collecting duct development, by S-shaped body stage, before differentiation of the proximal tubule, the loop of Henle and the distal tubule are complete. This connection allows the excretory products produced by the kidney to be removed and subsequently transferred, via the ureter, into the bladder where they are stored until it is appropriate to empty the bladder.

Thus, while the ureteric bud tissue differentiates into the drainage system of the definitive kidney, the metanephric mesenchymal tissue differentiates into its excretory component. By this means, large numbers of nephrons are induced to form from the metanephric tissue, and each of these units, as indicated above, drains into the definitive bladder through the derivatives of the ureteric bud. As indicated above, further differentiation of the excretory component of the system subsequently occurs, with the formation in the nephrons of the proximal and distal tubules, sometimes called 'convoluted tubules' because of their shape when fully mature, and the loop of Henle. The most caudal part of the ureteric bud gives rise to the ureter. For details of the ascent of the kidneys, and their associated blood supply during this period, see Kaufman & Bard (1999).

Nephrogenesis and nephron differentiation
Nephrogenesis and nephron differentiation.
Top row: Nephrogenesis is the process whereby cells of the cap mesenchyme (dark blue) undergo a mesenchymal to epithelial transition to form a nephron. Left: Nephron differentiation is illustrated in this schematic diagram and proceeds from early nephron (dark purple) to mature nephron (light blue). Pretubular aggregates (PA) form from cap mesenchyme cells (dark blue), in a specific location underneath the ureteric tips, in response to signals from the ureteric tree. Renal vesicles (RV), Stage I nephrons, are immature epithelial vesicles. Comma-shaped bodies (CSB) have developed a cleft and are connected to the tips. S-shaped bodies (SSB, Stage II nephrons) have developed visceral and parietal epithelial layers in their proximal end and endothelial cells begin migrating into the cleft. Capillary loop stage nephrons (Stage III) have an immature capillary network and their tubules are located within the cortex, close to the periphery of the kidney. Maturing and mature nephrons (Stage IV) have developed a vascularised renal corpuscle and their tubules have differentiated into distinct tubular segments. The loops of Henle have descended into the medulla by TS23 (15 dpc). Right: Diagrammatic sagittal section of a TS23 (15 dpc) kidney showing the metanephros layers; nephrogenic zone, cortex, medulla and pelvis.
Bottom row: Left: Schematic diagrams show 3-dimensional views of the kidney and ureter at TS20 (12 dpc) and TS23 (15 dpc). At TS20, the kidneys are comprised of a renal capsule, cap mesenchyme (dark purple), nephrogenic interstitium (light purple), the ureteric tree (brown) and developing nephrons including pretubular aggregates, renal vesicles and comma-shaped bodies. By TS23 (15 dpc), all nephron stages are seen in the kidney and the most mature nephrons present are referred to as maturing nephrons (Stage IV). Nephron structures in the periphery of the kidney (dark blue) include; PA, RV, CSB, S-shaped bodies, capillary loop stage nephrons and the renal corpuscles and cortical tubules of maturing nephrons. Loops of Henle of maturing nephrons are located in the centre of the kidney (light blue). Ureteric tips (brown) are also located on the surface of the kidney. Right: By TS28 (adult), nephrogenesis has ceased, there is no nephrogenic zone and all nephrons have matured, having developed distinct tubular segments. The kidney is subdivided into cortex, outer medulla (inner and outer stripes), inner medulla (often called papilla) and pelvis. Renal corpuscles (blue circles) are only present in the cortex, however, different tubular nephron segments are located in different regions of the kidney. During postnatal development, the inner medulla extends into the proximal ureter. Collecting ducts (brown) form the drainage system of the kidney which opens into the ureter. For a complete list of the structures present in each region of the kidney refer to the ontology pages.

Diagram shows a representative sagittal section through the kidney and illustrates the structures present at TS23 (15 dpc).

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Segmentation of the nephron
The development of the nephron from, renal vesicle (stage I nephron), through to the mature nephron is shown. Click on the arrows to view these different stages. The renal vesicle elongates to become a comma-shaped body and then an S-shaped body (stage II nephron). The developing capillary loop nephron (stage III nephron) is marked by the development of the glomerulus and elongation of the distal nephron segments to form the proximal tubule, loop of Henle and distal tubule.

Anatomical structures of the developing kidney.
Click on the arrows above to view these different structures. Anatomical structures represented include: 1-2) surface and sub-surface structures; 3) deeper structures; 4) developing nephrons; 5) ureteric bud and its derivatives; 6) ureter.

The development of the murine bladder

Before discussion of the development of the external genitalia, it is appropriate to discuss the development of the bladder here. As will be seen, this is a complex organ. It initially has a common origin with the caudal part of the hindgut, and is first evident at about TS15 (9.5 dpc). By about TS17 (10.5 dpc), this whole region then dilates to form the cloaca, and accordingly initially possesses an endodermal lining. The cloacal membrane develops where the cloaca makes contact with the overlying surface ectoderm and, characteristically, no intervening mesoderm develops in this location. On either side of the latter, the surface ectoderm is elevated to form the two genital folds (see below). A shallow depression forms in the region between the two genital folds. Shortly afterwards, at about TS17 (10.5 dpc), the first evidence of the substantial down growth, termed the urorectal septum is seen. This will, by about TS19-20 (11.5-12 dpc), completely separate the dorsally located future hindgut region from the ventrally located urogenital sinus. Most of the hindgut region at this stage is suspended by an elongated dorsal mesentery. With the division of the cloaca into these two distinct regions, the cloacal membrane becomes subdivided into a dorsally located anal membrane, and a ventrally located urogenital membrane. In the case of humans the future fibrous perineal “body” (also termed the central tendon of the perineum) then develops in the midline between the latter two membranes. A similar structure develops in the mouse.

Development of the bladder and urethra TS19-TS25
Development of the bladder and urethra– TS19 to TS25.
From left to right, schematic diagrams show the developing lower urogenital system at TS19 (11.5 dpc), TS20 (12 dpc), TS21 (13 dpc) and TS25 (17 dpc). The images are male, however the urinary systems of male and female are identical until approximately TS24 (16 dpc). Diagrams are representative of sagittal sections through the midline. Major organs include the cloaca (CL), genital tubercle (GT), caudal urogenital sinus (CUGS), primitive bladder (PBL), bladder (BL), pelvic urethra (PLUR), penile urethra (PNUR), penis, and scrotal fold (which will become the scrotum). The epithelium lining the lumen of the bladder and urethra (dark purple) is derived from cloacal endoderm. The nephric duct (nd), common nephric duct (cnd), ureteric bud (ub) and later the ureter (ur) are shown in orange and the paramesonephric duct (pnd) is shown in blue. The urogenital sinus grows out from the anterior side of the cloaca. It is subdivided into the primitive bladder and caudal urogenital sinus. The caudal urogenital sinus becomes the pelvic urethra at TS21 and the primitive bladder becomes the bladder at TS22. The urethral plate epithelium (or urethral plate), develops as an outgrowth of the cloacal epithelium, located along the ventral midline of the GT. It will form the epithelium of the phallic urethra (PHUR), located within the genital tubercle, later becoming the penile (PNUR) and clitoral urethra located within the penis and clitoris in the adult mouse. By TS20, the mesenchymal layer of the primitive bladder can be subdivided into inner (light blue) and outer regions and by TS21, smooth muscle cells which differentiate from the mesenchyme, are present in the fundus, or dome, of the primitive bladder (dark blue). Muscle differentiation progresses towards the bladder neck and pelvic urethra, forming the detrusor muscle of the bladder. Initially (TS19, left diagram), the ureteric bud stalk connects to the nephric duct and below this site, the common nephric duct connects to the sides of the urogenital sinus. Growth of the urogenital sinus and remodelling of the common nephric duct results in repositioning of the ureter (ur) orifice directly into the primitive bladder at TS21. By TS25 in the male only, prostate gland buds (purple) can be seen budding from the epithelium of the pelvic uretha, and the nephric duct has become the seminal vesicle (sv, orange), connected to the pelvic urethra via the ejaculatory duct. For more information on the anatomical differences between males and females, refer to the reproductive system tutorial page. Diagram modified from: An illustrated anatomical ontology of the developing mouse lower urogenital tract. Georgas et al.

Because the caudal one-third of the future anal canal is formed by the indentation of the surface ectoderm, to form the anal pit (or proctodaeum), this region constitutes the most caudal part of the future gastrointestinal tract. It subsequently develops into the lower one-third of the future anal canal, and consequently has an ectodermal lining. By contrast, the most caudal part of the embryonic hindgut forms the upper two-thirds of the anal canal, and is therefore lined by endoderm. These two regions fuse, and the region of fusion soon canalises. The relatively bloodless site of fusion is sometimes termed the pectinate line (or Hilton’s white line). The cloacal sphincter, being the derivative of the cloacal membrane, gives rise to the external anal sphincter, dorsally, and to the urogenital diaphragm, ventrally. Branches of the pudendal nerves subsequently supply both of these sphincters. By about TS20-21 (12-13 dpc), the endodermally derived urogenital sinus initially forms all of the lining of the future bladder, with the urachus at its apex. The latter structure is directed ventrally and slightly rostrally towards the umbilical region, and indeed runs in the umbilical cord. Initially, it contains a lumen that remains canalised until shortly before birth. The most rostral part of the urogenital sinus gives rise to the majority of the lining of the bladder, and the most caudal part is believed to give rise to its urethral derivatives, although exactly which parts has yet to be determined (see above).

Initially, the ureteric bud emerges from the caudal portion of the nephric duct following the physical connection between the caudal end of the nephric duct and the wall of the urogenital sinus. Technically, therefore, the ureter is thus not directly connected with the bladder, the final insertion site. In order to establish direct connections with the bladder, the caudal ureteric bud (the future ureter orifice) undergoes transposition. During this process, the base of the nephric duct including the ureteric bud stalk (the common nephric duct) becomes absorbed into the urogenital sinus, establishing a direct connection between the future ureter orifice and the primitive bladder. At the same time, degeneration of the common nephric duct occurs via an apoptotic mechanism, enabling the ureter to separate from the nephric ducts. Once separated from the nephric duct, the position of the ureter orifice shifts further anterior as the surrounding urogenital sinus tissue undergoes growth and expansion forming the bladder.

What is also evident, is that by the time of birth the wall of the bladder is thick and muscular. The latter constitutes the detrusor muscle. What is also evident is that the mucous membrane that lines the bladder, the urotheloum of the bladder, is of the transitional variety, while the loose nature of the submucosa, the lamina propria of the bladder, allows the mucosa of the empty bladder to be thrown into numerous folds.

Anatomy of the urinary system at TS23 (15dpc)
Anatomy of the urinary system at TS23 (15dpc).
Top row: Schematic diagrams show 3-dimensional views of the urogenital system at TS23 (15 dpc). The images are male, however the anatomy of the urinary system organs is identical in males and females at this stage. The nephric ducts (nd) and their anterior derivatives in the male, the epididymis, are shown in orange and the paramesonephric ducts are shown in blue. The kidneys are shown and their ureteric tips (orange) and the surrounding cap mesenchyme (purple) can be seen on their surface. The urothelium of the ureters and the epithelial lining of the kidney pelvis are shown in orange. The location of the pelvic ganglia (white spheres) and their neural processes (dotted white lines) are shown extending across the pelvic urethra and towards the bladder fundus (or dome).
Bottom row: Schematic diagrams show cross sections through the pelvic urethra (left, dorsal view), bladder (centre, ventral view) and both organs (right, lateral view) at TS23. The reproductive ducts connect to the anterior, dorsal pelvic urethra at a thickened region of its epithelium called the urogenital sinus ridge. The ureters enter the bladder within the neck region, close to the bladder-pelvic urethra junction. Blood vessels adjacent to the ureters can also be seen. The ureters are comprised of extravesicular (external to the bladder) and intravesicular (within the bladder wall) regions, and their orifices open within the bladder trigone. The bladder is divided into regions; the fundus, or dome, the blind end of the bladder and the neck, the narrow, open end of the bladder (right image). The trigone is the triangular-shaped, dorsal region of the bladder neck, its base is formed by the ureter orifices and its apex is the opening of the pelvic urethra. Diagrams modified from: An illustrated anatomical ontology of the developing mouse lower urogenital tract. Georgas et al.

Tissue layers of the bladder
Tissue layers of the bladder. Schematic diagrams show sections of the developing bladder at TS23 (15 dpc), TS25 (17 dpc) and TS28 (adult). The images are male, however the tissue layers of the bladder are identical in males and females. Major organs include the bladder (BL), pelvic urethra (PLUR) and prostatic urethra (PRUR, only present in the male). The ureter (ur), the nephric duct (nd) and its derivatives in the male, the ejaculatory duct (ed) and seminal vesicle (sv) are shown in orange.
Top row left: Diagram is representative of a cross section through the centre of the bladder at TS23 and shows the regions of the bladder from fundus (left) to neck (right). The trigone is the triangular-shaped, dorsal region of the bladder neck from the ureter orifices to the opening of the pelvic urethra (dotted grey line).
Top row right: A slice through the bladder wall shows the tissue layers present in the bladder from TS23 to 28.
Bottom row: Diagrams are representative of sagittal sections through the midline of the bladder and pelvic urethra at TS25 and TS28. Folds that develop in the urothelium give the adult bladder its characteristic appearance. At TS25 in the male only, prostate gland buds (pr buds, purple) can be seen budding from the epithelium of the anterior pelvic urethra. These will become the prostate glands (prgl) in the adult male (TS28). For more information on the anatomical differences between males and females, refer to the reproductive system tutorial page. Diagrams modified from: An illustrated anatomical ontology of the developing mouse lower urogenital tract. Georgas et al.

Observations on urinary development obtained from the analysis of staged histologically sectioned mouse embryos

The principal information about the stages of development when the initial features of the renal system are observed has been obtained from the detailed analysis of serially sectioned mouse embryos isolated at sequential stages of development. For further information, see the following sources: Theiler (1972, or 1989); Kaufman (1994, or subsequent reprints). For anatomical database, see: Kaufman & Bard (1999). For additional information, see also the anatomical ontology prepared by M. Little et al. (2007)  A high-resolution anatomical ontology of the developing murine genitourinary tract. Gene Expr Patterns. 7(6):680-99. 

TS12 (about 8 dpc): The first appearance of the intermediate plate mesoderm is seen, and this approximately corresponds with the first appearance of the somites.

TS13-15 (about 8.5-9.5 dpc): First evidence of nephrogenic cord formation and the differentiation of its most rostral part to form the pronephros. Later, the nephrogenic cord differentiates into the urogenital ridge. Mesonephric tubules are first recognised (at about TS15), and these drain into the mesonephric duct that is clearly seen to be patent along its length. The duct extends caudally towards the urogenital sinus.

TS16-17 (about 10-10.5 dpc): Mesonephric tubules are now clearly seen, as are mesonephric vesicles. The first evidence of the urorectal septum is seen, and will soon separate the hindgut from the urogenital sinus, and divide the cloacal septum into hindgut and urogenital components.

TS18-19 (about 11-11.5 dpc): The first evidence of differentiation of the metanephric region (caudal component) of the nephrogenic cord is first seen, although much of the mesonephros with its mesonephric ducts and vesicles are still present. The ureteric buds (sometimes termed the metanephric ducts) are also first seen at this stage. By TS19, the first evidence of branching of the ureteric bud derivatives within the nephrogenic interstitium (peripheral blastema) is also noted.

TS20-21 (about 12-13 dpc): The future renal cortex of the metanephros (now clearly the definitive kidney) is recognizable, and shows evidence of peripheral blastema and early nephrons. It should be noted that the primitive S-shaped bodies are more readily seen at TS21 of development than at TS20. The medullary component of the future kidney is now also delineating. As far as the “drainage” component of the future kidney is concerned, branching of the ureteric bud tissue is now clearly seen. This gives rise to the renal pelvis associated with the presence of a number of primitive renal collecting ducts within the hilar region of the kidney. As the general location of the kidneys rise rostrally within the peritoneal (or abdominal) cavity, the ureters correspondingly increase in length, and are clearly seen to be patent from an early stage of their differentiation. The mesonephros at this stage has now almost completely regressed.

TS22-23 (about 14-15 dpc): Early nephrons are now seen in the cortical region of the kidney as are numbers of maturing glomerular tufts, while medullary interstitium (stromal cells) are dispersed throughout much of the renal medulla. By TS23, the outermost region of the kidney now shows evidence of differentiation into a well-defined renal capsule, while the rest of the kidney is clearly subdivided into an outer renal cortex, subjacent to which is a zone that represents the region occupied by the cap mesenchyme tissue. There is also an inner medullary region. With regard to the ureteric bud-derived tissue, the renal pelvis is now clearly seen. The primitive collecting ducts and the ureter are also showing increased evidence of differentiation.

TS24-25 (about 16-17 dpc): In the cortical region of the kidney, proximal and distal tubules are first recognised, as well as glomerular tufts and Bowman’s capsules. In relation to the drainage system of the kidney, collecting ducts are also now clearly recognised.

TS26 (about 18 dpc): Within the renal cortex, the region subjacent to the capsule contains all components of the excretory system, including large numbers of glomerular tufts and the associated proximal and distal tubules (although these may occasionally be seen at earlier stages of development). The associated ascending and descending components of the loops of Henle, also termed the immature loops of Henle at this stage, may also be seen within the renal medulla. This region is now seen to contain considerably less undifferentiated mesenchyme tissue than formerly appeared to be the case. All of the components of the drainage system are now present and readily recognised, including the renal pelvis and the collecting tubules. They also now appear to possess a distinct endothelial lining. The ureter is also clearly seen, although readily recognised from about TS21. At all stages, the ureters are surrounded by a substantial amount of mesenchyme tissue.


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