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I./1.2.: Ontogeny of the uropoetic system and urinary passages
I./1.2.1.: Introduction
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The kidneys and ureters are derivatives of intermediate mesoderm (gononephrotome), connecting the paraxial and lateral mesoderms, whereas the urinary bladder and proximal urethra develop from endodermal epithelium of the cloaca, in particular the urogenital sinus. The ontogeny of kidneys and urinary passages involves highly complex processes of cellular differentiation, migration and proliferation, whose disturbances often result in developmental disorders. Disorders of the uropoetic system and urinary passages comprise 35-40 % of all embryonic malformations.
I./1.2.2.: Development of the kidneys
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In the course of embryonic development, three, in part overlapping, primordia of kidneys appear along the cranio-caudal body axis: pronephros, mesonephros and metanephros. The most cranially placed pronephros is the first to appear but it regresses a few days after appearance. Pronephros is then followed by mesonephros of thoracic position, which is functional as an excretory organ for a short while, after which it regresses, similarly to pronephros. Finally, the most caudal part of intermediate mesoderm, metanephros differentiates to yield major part of the functional adult kidney.
I./1.2.2.1.: Pronephros
Pronephros is the functional type of kidney in primitive vertebrates; in humans it appears in a rudimentary form at the level of cervical somites 2-6 on embryonic day 22, undergoing regression very soon, by day 25. Segmentation, characteristic for somites, also extends to the mesoderm of pronephros, whose segmented anlages (nephrotomes) are appended to the somites through short stems.
Due to mesenchymal transformation, mesodermal cells of the nephrotomes form hollow tubules with epithelial lining (pronephric tubules). The pronephric tubules of neighbouring nephrotomes turn in a caudal direction and, by gradual fusion and lengthening, they form the so called pronephric duct. Though pronephric tubules themselves regress within a couple of days, this does not affect the caudal portion of pronephric duct. The persisting part of pronephric duct extending toward the cloaca of the embryo will give rise to the initial portion of Wolffian duct (mesonephric duct), thereby inducing formation of the next primordium of kidney, mesonephros.
I./1.2.2.2.: Mesonephros
The next stage of development of the kidney is the formation of mesonephros, which starts to develop, already at the time of existing pronephros, from the so called unitary mesonephrogenic cord, an intermediate mesodermal anlage stretching between the somites C6 and L3. In week 4 of embryonic development, the cells of the unitary mesonephrogenic cord form groups and differentiate into epithelial cells, induced by the pronephric duct. The groups of condensed epithelial cell give rise to hollow mesonephric vesicles. The latter establish connection with the laterally situated pronephric duct through epithelial tubules and, after fusion, they give rise to the united Wolffian duct (mesonephric duct). By engulfing capillary loops arising from the aorta, the medial end-bits of mesonephric tubules (shaped as double walled cups) form the glomeruli of mesonephros. Although the latter are more advanced than the primitive glomeruli of pronephros, the development of mesonephros still gets retarded by the end of the second month, in fact, it largely regresses before the structural and functional appearance of metanephros. However, rather than regressing, the Wolffian duct continues to grow in a caudal direction and opens into the cloaca.
I./1.2.2.3.: Metanephros
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As the third stage of kidney development, the metanephros begins to develop in the embryonic week 5, from the intermediate mesoderm falling on the territory of lumbar somites 3-5 (metanephrogenic mesoderm), as wells as from the ureteric bud, a derivative of the mesonephric duct. Thus, the definitive kidney originates from two separate primordia, coming in contact as a result of a secondary process. The ureter, renal pelvis, calices and collecting ducts develop from the ureteric bud, whereas nephrons are derivatives of the metanephrogenic tissue of intermediate mesoderm. The ureteric bud arises caudally and dorsally from the cloacal site of entry of Wolffian duct, gradually penetrating the metanephrogenic mesoderm nearby.
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Thereafter, mesenchyme cells of metanephrogenic tissue tightly group around the epithelial cells of ureteric bud (mesenchymal condensation). A great deal of molecular details of the genetic occurrences regulating the subsequent complex mechanisms are now known. Cells of the metanephrogenic tissue express the transcription factor Pax-2. Lack of this factor causes severe developmental disorders of kidney in animal experimental models. In human, mutation of Pax-2 leads to renal coloboma syndrome, with kidney and retina defects. Following induction by the ureteric bud, HGF (hepatocyte growth factor) and GDNF (glial cell line-derived neurotrophic factor) are generated in the metanephrogenic tissue. Acting on tyrosine kinase receptors termed Met and Ret of the epithelial cells of ureteric bud, these factors promote lengthening and dichotomic branching of the ureteric bud.
At the same time, the ureteric bud also exerts an effect on the metanephrogenic tissue: it maintains continual division of mesenchymal cells through MBP-7 (bone morphogenetic protein-7) and FGF-2 (fibroblast-derived growth factor-2). Penetrating the metanephrogenic tissue, boat-shaped terminal varicosities of the ureteric bud give rise first to the primitive renal pelvis. The tubular and non-varicose caudal part of ureteric bud corresponds to the definitive ureter. By gradual growth, the ureteric bud branches further, to form primordia of the major and minor calices as well as the collecting ducts (tertiary branches). The distal end of the branches of ureteric bud determines further development of surrounding metanephrogenic tissue.
The ureteric bud induces differentiation of renal vesicles with epithelial lining. In the course of induction, metanephrogenic mesodermal cells express WT-1 gene (Wilms tumor suppressor 1; zinc finger transcription factor), promoting secretion of the growth factors GDNF and HGF. Moreover, the WT-1 gene affects the expression of Pax-2 in mesenchymal cells, and also the expression of other genes regulating GDNF signaling. This group comprises Sall1 (which causes the Townes-Brocks syndrome, including developmental disorders of the kidney, genitals, anus and heart) and the SIX1 and EYA1 genes (responsible for the bronchio-oto-renal syndrome). The onset of mesenchymal competition is followed by alteration of the expression of extracellular matrix proteins and cell adhesion molecules.
Characteristic for the basement mambrane of epithelial cells, the expression of laminin and collagen type IV takes place. In addition, adhesion molecules of syndecan and E-cadherin type, necessary for the condensation of mesenchymal cells and their epithelial transformation, become expressed on the surface of cells. The kidney vesicles turn into elongated S shaped tubules, one end of which forms a cap encapsulating the glomeruli arising from capillaries and differentiates into a nephron. At the proximal end of this nephron, the epithelial cells of the tubular cap will form the Bowman's capsule, while the distal end gives rise to the uriniferous tubules. Continually growing segments of uriniferous tubules develop into proximal convoluted tubules, the loop of Henle and distal convoluted tubules. In the beginning, the uriniferous tubules are not connected to the excretory duct system but later the cell layer separating them gets perforated, enabling the passage of urine.
The anlage of metanephros begins to develop in the pelvis (iliac fossa) below the bifurcation of aorta. Later, with the growth of lumbosacral region, the kidneys ascend into the abdominal cavity. Blood supply of the kidneys keeps changing in the course of this ascent. First it comes from the pelvic branches of the aorta, and then, in the end of migration, new blood vessels arise from higher segments of the aorta, whereas the lower vessels tend to regress simultaneously.
I./1.2.3.: Development of the urinary bladder and urethra
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Embryonic development of the bladder and urethra is associated with the caudal segment of hindgut, in particular the allantois, opening into the cloaca. The latter is a terminal swelling of hindgut, from which the allantois emerges in a ventral direction, whereas the vestigial tailgut continues caudally. Close apposition between the endodermal lining of the cloaca and the surface ectoderm gives rise to the cloaca membrane. The orifices of bilateral Wolffian ducts are situated at the site of transition between the allantois and cloaca.
Dorsally from this opening, mesenchymal cells of the wall of allantois penetrate the cloacal anlage to form the urorectal septum. By growing toward the cloaca mambrane, the urorectal septum gradually separates the cloaca into two cavities: anorectal canal (dorsally) and urogenital sinus (ventrally). The dorsal part gives rise to the rectum, whereas the anterior part of cloaca forms the anlage of the bladder (the part between the upper segment of allantois and the opening of the Wolffian ducts) as well as the secondary urogenital sinus, including the lower segments.
The cavity of the bladder extends cranially straight into the lumen of allantois. Later, in the second embryonic month this connection regresses and gets obliterated, the only persisting structure being a thin ligamentous cord (urachus), which connects the apex of bladder to the umbilicus as the median umbilical ligament. First, the Wolffian duct and the ureteric bud developing from it have a common opening in the wall of the cloaca. Following development of the urorectal septum, this area belongs to the anlage of the bladder and, in the next stage of differentiation, the distal part of the Wolffian duct (extending to the point of evagination of the ureter) gets incorporated into the wall of the bladder.
According to earlier assumption, the distal segment of mesonephric duct (between the ureteric bud and the bladder) together with the evaginating part of ureter become incorporated into the bladder wall, forming the trigone, due to intensive growth of the bladder. Following incorporation, the ureter and Wolffian duct move apart, leading to separate openings. However, studies on mouse embryos have proved the key role of apoptosis in the development of the distal segment of mesonephric duct. It has been clarified by now that separation of the ureter from the Wolffian duct is based upon programmed cell death, leading into regression of the common segment of mesonephric duct, rather than incorporation into the bladder wall, whereby the ureters and Wolffian ducts open separately into the trigone.
Owing to the ascent of kidneys, the ureteric orifices migrate in a cranial and lateral direction, whereas the Wolffian ducts come close to each other and sink to the caudal region of the bladder. The trigonum vesicae of mesenchymal origin, a continuation of the mucosal area falling between the ureteric and mesonephric orifices, corresponds, in the male, to the dorsal of wall of prostatic urethra as far as the opening of ejaculatory ducts, and, in the female, to the dorsal wall of the entire urethra. The prostatic urethra of the male represents that part of urethra which is surrounded by the prostate. The ventral wall of prostatic urethra as well as the membranous part of urethra are derivatives of the middle portion of secondary urogenital sinus.
The third and last segment of male urethra develops from the urethral groove (sulcus urethralis), which lies between the epithelial folds appearing in the lower region (phallic part) of the urogenital sinus. Fusion of the epithelial folds above the urethral groove leads to the formation of a tubular structure, the pars spongiosa of urethra. After forming the navicular fossa, a slight outpocketing in the glans penis, the spongy part of urethra opens to the exterior at the external ureteric orifice. The urethral segment situated in the navicular fossa develops from ectodermal epithelium covering the glans penis.
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