Development of kidney, ureter, bladder, urethra, internal and external genitalia

1. Embryology of the Genitourinary Tract

2. CONTENT
KIDNEY DEVELOPMENT
BLADDER AND URETER DEVELOPMENT
GENITAL AND REPRODUCTIVE TRACT DEVELOPMENT

3. OVERVIEW OF DEVELOPMENT UPTO 3 WEEKS

4. Embryologically, all three kidneys develop from the intermediate mesoderm.
As the notochord and neural tube develop, the mesoderm located on either side of
the midline differentiates into three subdivisions: paraxial (somite), intermediate,
and lateral mesoderm.
As the embryo undergoes transverse folding, the intermediate mesoderm separates
away from the paraxial mesoderm and migrates toward the intraembryonic coelom
(the future peritoneum).
At this time there is a progressive craniocaudal development of the bilateral
longitudinal mesodermal masses, called nephrogenic cords.
Each cord is seen bulging from the posterior wall of the coelomic cavity, producing
the urogenital ridge.
The intermediate mesoderm gives rise to paired, segmentally organized
nephrotomes from cervical to sacral region.

5. KIDNEY DEVELOPMENT
Three slightly overlapping kidney systems are formed in a cranial-to-
caudal sequence during intrauterine life in humans: the pronephros,
mesonephros, and metanephros.
The first of these systems is rudimentary and nonfunctional
Second may function for a short time during the early fetal period;
Third forms the permanent kidney
The intermediate mesoderm gives rise to paired, segmentally
organized nephrotomes from cervical to sacral region.

6. Pronephrons
Cervical nephrotomes are formed early during the fourth week
and are collectively referred to as the pronephros.
Pronephros develops in each of five to seven cervical
segments, but this primitive renal structure degenerates
quickly during the fourth week.
At the beginning of the fourth week, the pronephros is represented by 7 to 10 solid
cell groups in the cervical region. These groups form vestigial excretory units,
nephrotomes, that regress before more caudal ones are formed. By the end of the
fourth week, all indications of the pronephric system have disappeared.

8. Mesonephrons
The (meso)nephric ducts first appear on day 24.
Mesonephric vesicles and tubules form in a craniocaudal direction
throughout the thoracic and lumbar regions.
The cranial pairs degenerate as caudal pairs develop, and the definitive
mesonephros contains about 20 pairs confined to the first three
lumbar segments
Early in the fourth week of development, during regression of the
pronephric system, the first excretory tubules of the mesonephros
appear.
They lengthen rapidly, form an S-shaped loop, and acquire a tuft of
capillaries that will form a glomerulus at their medial extremity.

9. Around the glomerulus, the tubules form Bowman’s capsule, and
together these structures constitute a renal corpuscle.
Laterally, the tubule enters the longitudinal collecting duct known as
the mesonephric or wolffi an duct (nephric duct).
In the middle of the second month, the mesonephros forms a large
ovoid organ on each side of the midline.
Since the developing gonad is on its medial side, the ridge formed by
both organs is known as the urogenital ridge.
While caudal tubules are still differentiating, cranial tubules and
glomeruli show degenerative changes, and by the end of the second
month, the majority have disappeared.
In the male, a few of the caudal tubules and the mesonephric duct
persist and participate in formation of the genital system, but they
disappear in the female.

10. Metanephros:
The Definitive Kidney, the metanephros or permanent kidney, appears
in the fifth week.
Its excretory units develop from metanephric mesoderm in the same
manner as in the mesonephric system.
The definitive kidney, or the metanephros, forms in the sacral region
as a pair of new structures, called the ureteric buds, sprout from the
distal portion of the nephric duct and come in contact with the
condensing blastema of metanephric mesenchyme at about the 28th
day
The metanephric mesenchyme induces the ureteric bud to branch and
divide, and in turn the ureteric bud induces the metanephric
mesenchyme to condense and undergo mesenchymalepithelial
conversion.

12. The tip of the dividing ureteric bud induces the metanephric
mesenchyme to condense, which then differentiates into a renal
vesicle.
This vesicle coils into an S-shaped tubule and ultimately forms a
Bowman capsule as well as the proximal convoluted tubules, distal
convoluted tubules, and loops of Henle.
Dichotomous branching of the ureteric bud and subsequent fusion of
the ampullae to form the renal pelvis and calyces
The metanephric mesenchyme contribute to the formation of
nephron, which consists of the glomerulus, proximal tubule, loop of
Henle, and distal tubule.
The ureteric bud contributes to the formation of the collecting system,
consisting of collecting ducts, calyces, pelvis, and ureter.

13. Collecting System
The dichotomous branching of the ureteric bud determines the
eventual pelvicalyceal patterns and their corresponding renal lobules
Between 22 and 24 weeks of human fetal gestation the peripheral
(cortical) and central (medullary) domains of the developing kidney
are established.
Collecting ducts of the permanent kidney develop from the ureteric
bud, an outgrowth of the mesonephric duct close to its entrance to the
cloaca.
The bud penetrates the metanephric tissue, which is molded over its
distal end as a cap.
Subsequently, the bud dilates, forming the primitive renal pelvis, and
splits into cranial and caudal portions, the future major calyces

15. Each calyx forms two new buds while penetrating the metanephric
tissue.
These buds continue to subdivide until 12 or more generations of
tubules have formed.
Meanwhile, at the periphery, more tubules form until the end of the fi
fth month.
The tubules of the second order enlarge and absorb those of the third
and fourth generations, forming the minor calyces of the renal pelvis.
During further development, collecting tubules of the fi fth and
successive generations elongate considerably and converge on the
minor calyx, forming the renal pyramid.
The ureteric bud gives rise to the ureter, the renal pelvis, the major
and minor calyces, and approximately 1 to 3 million collecting tubules.

16. Hence, the kidney develops from two sources:
(1)metanephric mesoderm, which provides excretory units and
(2)ureteric bud, which gives rise to the collecting system.
Nephrons are formed until birth, at which time there are
approximately 1 million in each kidney.
Urine production begins early in gestation, soon after differentiation
of the glomerular capillaries, which start to form by the 10th week.
At birth, the kidneys have a lobulated appearance, but the lobulation
disappears during infancy as a result of further growth of the
nephrons, although there is no increase in their number.

17. Renal Ascent
Between the sixth and ninth weeks the kidneys ascend to a lumbar
site just below the adrenal glands
The precise mechanism responsible for renal ascent is not known, but
it is speculated that the differential growth of the lumbar and sacral
regions of the embryo plays a major role.
During ascent the fused lower pole becomes trapped under the
inferior mesenteric artery and thus does not reach its normal site

18. Molecular Mechanism of Kidney Development
Formation of renal tubules and the collecting system occurs
sequentially and requires dynamic interactions among epithelial,
mesenchymal, and stromal cells.
The early intermediate mesoderm destined to become nephric ducts is
distinguished by expression of the transcription factors LIM1, PAX2,
and SIM1, but only LIM1 appears to be absolutely essential for nephric
duct formation.
Epithelium of the ureteric bud from the mesonephros interacts with
mesenchyme of the metanephric blastema.

19. The mesenchyme expresses WT1, a transcription factor that makes
this tissue competent to respond to induction by the ureteric bud
WT1 also regulates production of glialderived neurotrophic factor
(GDNF) and hepatocyte growth factor (HGF, or scatter factor) by the
mesenchyme, and these proteins stimulate branching and growth of
the ureteric buds.
The tyrosine kinase receptors RET, for GDNF, and MET, for HGF, are
synthesized by the epithelium of the ureteric buds, establishing
signaling pathways between the two tissues.
In turn, the buds induce the mesenchyme via fi broblast growth factor
2 (FGF2) and bone morphogenetic protein 7 (BMP7).

20. Both of these growth factors block apoptosis and stimulate
proliferation in the metanephric mesenchyme while maintaining
production of WT1.
Conversion of the mesenchyme to an epithelium for nephron
formation is also mediated by the ureteric buds through expression
of WNT9B and WNT6, which upregulate PAX2 and WNT4 in the
metanephric mesenchyme.
PAX2 promotes condensation of the mesenchyme preparatory to
tubule formation. WNT4 causes the condensed mesenchyme to
epithelialize and form tubules.

21. Because of these interactions, modifi cations in the extracellular
matrix also occur.
Thus, fi bronectin, collagen I, and collagen III are replaced with laminin
and type IV collagen, characteristic of an epithelial basal lamina.
In addition, the cell adhesion molecules syndecan and E-cadherin,
which are essential for condensation of the mesenchyme into an
epithelium, are synthesized

22. BLADDER AND URETER DEVELOPMENT
At the third week of gestation the cloacal membrane remains a
bilaminar structure composed of endoderm and ectoderm.
During the fourth week the neural tube and the tail of the embryo
grow dorsally and caudally, projecting over the cloacal membrane, and
this differential growth of the body results in embryo folding.
The cloacal membrane is now turned to the ventral aspect of the
embryo, and the terminal portion of the endoderm-lined yolk sac
dilates and becomes the cloaca.
According to the theories of Rathke and Tourneux regarding embryonic
development, the partition of the cloaca into an anterior urogenital
sinus and a posterior anorectal canal occurs by the midline fusion of
two lateral ridges of the cloacal wall and by a descending urorectal
septum.

23. The nephric (wolffian) duct fuses with the cloaca by the 24th day and
remains with the urogenital sinus during the cloacal separation.
The entrance of the nephric duct into the primitive urogenital sinus
serves as a landmark distinguishing the cephalad vesicourethral canal
from the caudal urogenital sinus.
The vesicourethral canal gives rise to the bladder and pelvic urethra,
whereas the caudal urogenital sinus forms the phallic urethra for
males and distal vaginal vestibule for females

24. By day 33 of gestation, the common excretory ducts (the portion of
nephric ducts distal to the origin of ureteric buds) dilate and connect
to the urogenital sinus.
The formation of these final connections involves apoptosis, which
enables the ureters to disconnect from the nephric ducts, and fusion,
in which the ureteral orifice inserts into the urogenital sinus
epithelium at the level of the trigone .
According to the classic view (Weiss, 1988), the right and left common
excretory ducts fuse in the midline as a triangular area, forming the
primitive trigone, structurally different from bladder and urethra

25. The ureter begins as a simple cuboidal epithelial tube surrounded by
loose mesenchymal cells that acquires a complete lumen at 28 days of
gestation in humans.
During differentiation of the cloaca, the caudal portion of the
mesonephric ducts are absorbed into the wall of urinary bladder.
Consequetly the ureters, initially outgrowths from the mesonephric
ducts, enter the bladder separately, the orifices of the ureters move
farther cranially; those of the mesonephric ducts move close together
to enter the prostatic urethra and in the male become the ejaculatory
ducts.
Since both the mesonephric ducts and ureters originate in the
mesoderm, the mucosa of the bladder formed by incorporation of the
ducts (the trigone of the bladder) is also mesodermal.

26. With time, the mesodermal lining of the trigone is replaced by
endodermal epithelium, so that fi nally, the inside of the bladder is
completely lined with endodermal epithelium.
The epithelium of the urethra in both sexes originates in the
endoderm; the surrounding connective and smooth muscle tissue is
derived from visceral mesoderm.
At the end of the third month, epithelium of the prostatic urethra
begins to proliferate and forms a number of outgrowths that
penetrate the surrounding mesenchyme.
In the male, these buds form the prostate gland.
In the female, the cranial part of the urethra gives rise to the urethral
and paraurethral glands

27. GENITAL AND REPRODUCTIVE TRACT DEVELOPMENT
During the fifth week, primordial germ cells migrate from the yolk sac
along the dorsal mesentery to populate the mesenchyme of the
posterior body wall near the 10th thoracic level
The arrival of primordial germ cells in the area of future gonads serves
as the signal for the existing cells of the mesonephros and the adjacent
coelomic epithelium to proliferate and form a pair of genital ridges just
medial to the developing mesonephros.
During the sixth week the cells of the genital ridge invade the
mesenchyme in the region of future gonads to form aggregates of
supporting cells called the primitive sex cords.
The primitive sex cords will subsequently invest the germ cells and
support their development.

29. The genital ridge mesenchyme containing the primitive sex cords is divided into
the cortical and medullary regions.
Both regions develop in all embryos, but after the sixth week they pursue
different fates in the male and female
During this time a new pair of ducts, called the paramesonephric (müllerian)
ducts, begins to form just lateral to the nephric ducts in both male and female
embryos.
These ducts arise by the craniocaudal invagination of thickened coelomic
epithelium, extending all the way from the third thoracic segment to the
posterior wall of the developing urogenital sinus.
The caudal tips of the paramesonephric ducts adhere to each other as they
connect with the urogenital sinus between the openings of the right and left
nephric ducts.
The cranial ends of the paramesonephric ducts form funnel-shaped openings
into the coelomic cavity, which is the future peritoneum.

30. In both male and female embryos, these cords are connected to
surface epithelium and it is impossible to differentiate between the
male and female gonad hence called indifferent gonads
The indifferent gonads differentiate into cortex and medulla.
Medulla regresses in embryos with an XX sex chromosome complex
whereas in XY sex chromosome complex, medulla differentiate into
testis but cortex regresses

31. Male and female gonad and genital development.
The male and female genital structures are virtually identical through
the seventh week.
Males embryo
SRY protein produced by the Sertoli cells causes the medullary sex
cords to become presumptive seminiferous tubules and causes the
cortical sex cords to regress.
Müllerian-inhibiting substance (MIS), a glycoprotein hormone
produced by the Sertoli cells, then causes the paramesonephric ducts
to regress, leaving behind appendix testis and prostatic utricle as
remnants.
Appendix epididymis and paradidymis arise from the mesonephric
ducts.

32. Female embryos
The primitive sex cords do not contain the Y chromosome, do not elaborate SRY
protein, and therefore do not differentiate into Sertoli cells.
In the absence of Sertoli cells and SRY protein, therefore, MIS synthesis, Leydig
cell differentiation, and androgen production do not occur.
Consequently, male development of the genital ducts and accessory glands is not
stimulated and female development ensues.
In females, cortical sex cords invest the primordial germ cells and become the
ovarian follicles.
In the absence of MIS, the mesonephric ducts degenerate and the
paramesonephric ducts give rise to the fallopian tubes, uterus, and upper two
thirds of the vagina .
The remnants of the mesonephric ducts are found in the ovarian mesentery as
the epoöphoron and paroöphoron, and in the anterolateral vaginal wall as the
Gartner duct.

34. Development of male accessory sex glands.
During the 10th week, the seminal vesicles sprout from the distal
mesonephric ducts in response to testosterone
The prostate and bulbourethral glands develop from the urethra in
response to dihydrotestosterone.
Thus the vas deferens and seminal vesicle derive from the
mesonephric ducts (MS), and the prostate and bulbourethral glands
develop from the urogenital sinus (UG) and UB from ureteric bud

35. Development of Female Genital Structures
The distal tips of the paramesonephric ducts adhere to each other just before
they contact the posterior wall of the urogenital sinus.
The wall of the urogenital sinus at this point forms a small thickening called the
sinusal tubercle.
As soon as the fused tips of the paramesonephric ducts connect with the sinusal
tubercle, the paramesonephric ducts begin to fuse in a caudal to cranial
direction, forming a tube with a single lumen.
This tube, called the uterovaginal canal, becomes the superior portion of the
vagina and the uterus.
The unfused, superior portions of the paramesonephric ducts become the
fallopian tubes (oviducts), and the funnel-shaped superior openings of the
paramesonephric ducts become the infundibula
The most inferior portion of the uterovaginal canal becomes occluded transiently
by a block of tissue called the vaginal plate

37. As the vaginal plate forms, the lower end of the vagina lengthens, and
its junction with the urogenital sinus migrates caudally until it comes
to rest on the posterior wall of definitive urogenital sinus (future
vestibule of the vagina) during the fourth month.
An endodermal membrane temporarily separates the vaginal lumen
from the cavity of the definitive urogenital sinus.
This barrier degenerates partially after the fifth month, but its
remnant persists as the vaginal hymen.
The mucous membrane that lines the vagina and cervix may also
derive from the endodermal epithelium of the definitive urogenital
sinus

38. Development of External Genitalia
The early development of the external genitalia is similar in both sexes.
Migrating mesenchymal cells spread themselves around the cloacal membrane
and pile up to form swellings.
Early in the fifth week, a pair of swellings called cloacal folds develops on either
side of the cloacal membrane.
These folds meet just anterior to the cloacal membrane to form a midline
swelling called the genital tubercle.
During the cloacal division into the anterior urogenital sinus and the posterior
anorectal canal, the portion of the cloacal folds flanking the opening of the
urogenital sinus becomes the urogenital folds and the portion flanking the
opening of the anorectal canal becomes the anal folds.
A new pair of swellings, called the labioscrotal folds, appears on either side of
the urogenital folds

40. The external genitalia derive from a pair of labioscrotal swellings, a pair of
urogenital folds, and an anterior genital tubercle.
Male and female genitalia are morphologically indistinguishable until the
seventh week.
In males :
the urogenital folds fuse and the genital tubercle elongates to form the penile
shaft and glans.
A small region of the distal urethra in the glans is formed by the invagination of
surface epithelial tag.
The fused labioscrotal folds give rise to the scrotum.
In females:
The genital tubercle bends inferiorly to form the clitoris, and the urogenital folds
remain separate to become the labia minora.
The unfused labioscrotal folds form the labia majora

41. Development of external genitalia occurs via three main pathways:
(1) androgen independent,
(2) androgen dependent, and
(3) endocrine and environmental influence
The molecular basis of the sexual dimorphism in genital development is based
on the presence or absence of the signaling via the androgen receptor.
During embryonic weeks 9 and 10 SRY (sex-determining region of Y
chromosome) causes differentiation of Leydig cells, which produce
testosterone.
In the presence of fetal testicular androgens the wolffian ducts persist and
develop into the epididymis, vas deferens, and seminal vesicles
In the female, because of the absence of androgen receptor signaling via DHT,
the primitive perineum does not lengthen and the labioscrotal and urethral
folds do not fuse across the midline.
The phallus bends inferiorly, becoming the clitoris, and the ostium of the
urogenital membrane becomes the vestibule of the vagina.

42. Mechanism of gonadal descent
The undifferentiated gonad is initially located high in the abdomen, anchored
by the cranial suspensory ligament (CSL).
In males
Insl3 will cause the swelling and enlargement of the gubernaculum to pull the
developing testis toward the inguinal region
androgens will cause an involution of CSL.
Owing to the action of müllerian-inhibiting substance, müllerian ducts will
regress while androgens continue to stimulate the development of wolffian
ducts into male genital ductal structures.
In females
CSL persists because of the absence of androgens
the gubernaculum remains thin as a result of the absence of Insl3 activity
thereby keeping the ovary well within the pelvis.

44. Molecular mechanism of male and female genital development.
SF1 and WT1 expression is critical for genital ridge specification.
SRY and SOX9, influenced by GATA4 and Fog2, are important factors for
specifying the differentiation of Sertoli cells.
SF1 is also critical in the regulation of müllerian-inhibiting substance (MIS) and
other genes involved in androgen synthesis.
No specific female factors have been identified, but Wnt4 and DAX1 are
expressed with unique female patterns. DHT, dihydrotestosterone

45. The genitourinary system develops from three embryonic sources: intermediate
mesoderm, mesothelium of coelomic (future peritoneum) cavity, and endoderm of
the urogenital sinus.
• The urinary system begins its development before the genital system
development becomes evident. With the formation of nephric ducts, embryonic
kidneys develop sequentially in the order of pronephros, mesonephros, and
metanephros.
• The permanent kidney, the metanephros, develops as a result of inductive
interactions involving the ureteric bud (an outgrowth of nephric duct), condensing
blastema of metanephric mesenchyme, and stromal cells.
The renal tubulogenesis occurs via mesenchymal-epithelial conversion, whereas
dichotomous branching of the ureteric bud leads to the formation of the collecting
system.
• The bladder and urethra develop from the endodermal urogenital sinus, which is
an anterior portion of the cloaca after it becomes separated from the posterior
anorectal canal.
• Morphologically, the genital development takes place about 3 weeks after the
start of the urinary system development. Sexual dimorphism begins to take shape at
about the seventh gestational week. Primordial germ cells migrate from the wall of
the yolk sac to invade the posterior mesenchyme to establish the gonadal ridge.

46. • In males, driven by the SRY gene of the Y chromosome, mesenchymal cells of the
developing testis differentiate to become the Sertoli cells.
Sertoli cells produce MIS to cause degeneration of female müllerian ductal structures while
stimulating the development of testosterone-producing Leydig cells.
Under the influence of testosterone, male external genitalia develop, as well as prostate and
other male accessory sex glands.
• Both gonads descend to pelvic location by the third month, but the testis descends into the
scrotum with the aid of the gubernaculum at about the seventh month.

49. REFERENCES
•CAMPBELL-WALSH UROLOGY, ELEVENTH EDITION
•LANGMAN’S MEDICAL EMBRYOLOGY. — 12TH ED. / T.W. SADLER

50. THANK U
