Lecture 2: Renal Embryology

Question 1

what developmental events occur at week 3?

Answer 1

gastrulation, subdivision of mesodermal germ layer into paraxial, intermediate, and lateral mesoderm

at 3.5 weeks, the intermediate mesoderm extends on each side of embryo from cervical to sacral regions giving rise to 3 paired sets of excretory structures. Sacral components develop into adult kidney while cervical and thoraco-lumbar regions are transient.

Question 2

what developmental events occur during week 4?

Answer 2

formation of the pronephric duct, appearance and regression of pronephric tubules, appearance of mesonephric tubules

elongated duct forms within the intermediate mesoderm on each side of the embryo and extends from the cervical region to the expanded end of the hindgut (the cloaca). On each side of the embryo, interactions between this duct and the adjacent intermediate mesoderm lead to differentiation of excretory tubules.

Question 3

what developmental events occur during week 5?

Answer 3

appearance of adult kidney precursors (metanephric mesencyme and ureteric bud)

Question 4

What developmental events occur at week 6?

Answer 4

cranial (thoracic) mesonephros undergoes massive regression, caudal (lumbar) mesonephric tubules function, metanephric excretory units being formation
kidneys begin to ascend

Question 5

What developmental events occur at week 7?

Answer 5

division of the cloaca comple
regression of the allantois
rupture of the urogenital component of cloacal membrane

Question 6

What developmental events occur between weeks 9 and 10?

Answer 6

kidneys reach lumbar position
mesonephros cease to function and regress
metanephric kidney begins to function

Question 7

Describe the pronephric kidney (pronephros)

Answer 7

Consists of small epithelial clusters or rudimentary tubules in the cervical region; nonfunctional in
humans and present only during the 4th week. At early stages, the associated duct is called the pronephric duct. At later stages, this duct is known as the mesonephric or Wolffian duct as its primary association is with the mesonephros.

Question 8

Describe the mesonephric kidney (mesonephros)

Answer 8

Consists of clusters of tubules that form a large swelling in the thoraco-lumbar region. The duct associated with these tubules is the mesonephric duct (the original pronephric duct). Mesonephric tubules resemble simplified versions of adult excretory tubules and appear to function during the 2nd month of development. However, the tubules of the cranial mesonephros undergo extensive regression shortly after they form. The tubules of the caudal mesonephros ultimately regress as well, but some of their cellular components contribute to the gonads in males. The mesonephric ducts regress in females but form the epididymis and vas deferens in males

Question 9

Describe the metanephric kidney (metanephros)

Answer 9

It is the definitive kidney. Two embryonic
components contribute to the formation of each adult kidney: the ureteric bud and the metanephric mesenchyme. The ureteric bud emerges as a bud off the distal end of the mesonephric duct. Each bud penetrates intermediate mesoderm in the sacral region. This intermediate mesoderm is called the metanephric mesenchyme or metanephric blastema.

Question 10

Development of the ureteric bud and metanephric mesenchyme

Answer 10

Ureteric bud emerges from the mesonephric duct and undergoes repeated branching and elongation.
Metanephric mesenchyme condenses around the tips of ureteric bud and its branches. Cells of the metanephric mesenchyme undergo a transformation into epithelial cells and differentiate into the nephrons of the kidney.

Question 11

What does the ureteric bud give rise to?

Answer 11

ureter, renal pelvis, the calyses, and the collecting ducts and tubules

Question 12

What are the derivatives of the metanephric mesenchyme?

Answer 12

renal corpuscle (except the blood vessels), the loop of Henle, and the proximal and distal convoluted tubules.

Question 13

Where do the signals for differentiation of ureteric bud and metanephric mesenchyme come from?

Answer 13

Signals from metanephric mesenchym induce elongation and branching of the ureteric bud. Signals from the ureteric bud induce the aggregation of metanephric mesenchyme
cells and their subsequent differentiation into nephrons

Question 14

Ascent of the kidneys and changing arterial blood supply.

Answer 14

During late embryogenesis, the kidneys appear to ascend from a sacral position to a lumbar position. During ascent, the metanephric kidneys are supplied by segmental arteries that originally supplied the mesonephros. Usually, these vessels are reduced to a single pair of renal arteries in the
adult.

Question 15

What does the GDNF-Ret signaling do?

Answer 15

drives uteric bud outgrowth and branching by influencing cell movement and proliferation.

b. Some carriers of RET or GDNF mutations present with renal abnormalities as
well as Hirschsprung disease (intestinal aganglionosis).

Question 16

What is GDNF?

Answer 16

GDNF (Glial cell line derived growth factor) is a secreted factor produced by metanephric mesenchyme. It activates the RET receptor (a tyrosine kinase) and its co-receptor, GFRA1, located on mesonephric duct and ureteric bud cells.

Question 17

What disease is associated with carriers of RET or GDNF mutations

Answer 17

renal abnormalities and Hirschsprung disease (intestinal aganglionosis).
mutations in RET in 37% of fetuses with
bilateral agenesis and in 20% with unilateral agenesis

Question 18

What are the transcription factors that regulate GDNF?

Answer 18

EYA1
PAX2
Sall1
Hox11
Wnt11
WT1

Question 19

What defect and syndrome is associated with EYA1 mutation?

Answer 19

Renal agenesis or hypoplasia, Syndrome:

Branchio-oto-renal (BOR)

Question 20

What defect and syndrome are associated with PAX2 mutation?

Answer 20

Defect: Renal hypoplasia, Syndrome: Renal Coloboma

Question 21

What defect and syndrome are associated with SALL1 mutation?

Answer 21

Defect: Renal hypoplasia, Syndrome: Townes-Brocks

Question 22

What limits expression/function of GDNF to sacral regions?

Answer 22

Signaling via SLIT2 and its receptor ROBO2 may repress GDNF expression levels at more cranial
levels. BMP4 signaling may inhibit RET signaling in cranial parts of the mesonephric duct. The BMP inhibitor, Gremlin, blocks BMP signaling in the metanephric mesenchyme (i.e. allows outgrowth in the right region).

Question 23

What are diseases associated with mutations in ROBO2?

Answer 23

vesicoureteral reflux (VUR), megaureter, and dysplastic kidneys.

Question 24

What are diseases associated with mutations in BMP4?

Answer 24

congenital anomalies of the kidney and urinary tract (CAKUT).

Question 25

What do Wnt proteins do?

Answer 25

They are primary initiators of metanephric mesenchyme condensation and epithelial cell polarization. They are secreted molecules that signal via multiple pathways.

Question 26

what is the canonical pathway for Wnt proteins?

Answer 26

WNT binding to the Frizzled receptor leads
to an accumulation of -catenin in the cytoplasm, its translocation to the nucleus, and ultimately its regulation of target genes including those influencing cellular proliferation and differentiation.

Question 27

What is the purpose of Wnts from the uteric bud/?

Answer 27

major inducers of metanephric
mesenchyme aggregation and promote a mesenchymal to epithelial transition
(Wnt9b). They may also function in the maintenance/upregulation of GDNF (Wnt
11).

Question 28

What is the purpose of Wnts from the metanephric mesenchyme?

Answer 28

formation and polarization of epithelial cells of the nephron. (Wnt4)

Question 29

what is the purpose of the wilms tumor gene 1 (WT1)

Answer 29

It is involved in early and late phases of metanephric
kidney development.
At early stages, WT1 appears to regulate GDNF and promote the survival of metanephric mesenchyme progenitors. At later stages, WT1 may inhibit proliferation of these cells, leading instead to differentiation.

Question 30

What diseases are associated with mutations in WT1?

Answer 30

Mutations in WT1 are present in about 5-10% of Wilms tumors. Wilms tumor is the most common pediatric kidney cancer. The loss of WT1 may arrest nephron precursors in multipotent progenitor state. Subsequently, additional genetic events may transform these cells and cause uncontrolled growth.

Question 31

what is wilms tumor?

Answer 31

Wilms tumor is the most common pediatric kidney cancer. These tumors are thought to develop from clusters of mesenchyme (nephrogenic
rests) that may represent arrested nephrogenic progenitors or stem cells.

Question 32

What is the cloaca?

Answer 32

It is the end of the primitive gut tube and the central player in the development of the bladder and urethra The cloaca is continuous with allantois and hindgut.
Between the 4th and 7th weeks the cloaca is partitioned into the anorectal canal (continuous with the hindgut) and the urogenital sinus or UGS (continuous with the allantois). This is accomplished by the growth and rearrangement of mesoderm between and around the allantois and hindgut (originally called the urorectal septum).
Initially the cloacal membrane separates the cavity of the cloaca from the amniotic cavity. The cloacal membrane breaks down during the 7th and 8th weeks, thus opening the cavities of the urogenital sinus and the anal canal to that of the amnion.

Question 33

What is the allantois

Answer 33

a thin diverticulum that extends into the connecting stalk,

Question 34

What are the derivatives of the urogenital sinus?

Answer 34

The cranial part of the urogenital sinus expands to form the bladder. The more caudal
part of the urogenital sinus (the pelvic or genital portion) gives rise to the urethra in the
male and the urethra and vestibule of the vagina in the female.
Only the internal linings of these structures are derived from the endoderm of the urogenital sinus. Lateral mesodermal tissue forms the muscles and connective tissues. In addition an epithelial tag of tissue contributes to the distal tip of the male urethra

Additional derivatives of the urogenital sinus
Prostate gland - originates as buds from the prostatic region of the urethra.
Lower part of the vagina - derived from solid endodermal outgrowths of UGS

Question 35

Describe the regression of the allantois and bladder apex

Answer 35

The allantois and bladder apex regress during the second embryonic month. The remnants become a ligamentous band called the urachus or median umbilical ligament.

Question 36

Describe the displacement of the ureters

Answer 36

As the bladder is forming, the ureters become displaced from the mesonephric ducts to
the bladder wall. (The short common segment undergo apoptosis.) The ureters acquire a distinct and separate entry into the bladder. Second, the entry of the mesonephric duct (presumptive vas deferens) becomes positioned inferior to that of the ureter.

Question 37

Describe renal agenesis and its possible causes

Answer 37

failure of formation or degeneration of the ureteric bud. In the absence of appropriate signals the metanephric mesenchyme does not differentiate. . Renal agenesis may be associated with mutations in RET or EYA1. If renal agenesis is bilateral, oligohydramnios can occur (an insufficiency in amniotic fluid volume) and the fetus/neonate may show Potter sequence or syndrome. Abnormalities include clubbed feet, craniofacial abnormalities, and pulmonary hypoplasia.

Question 38

Describe duplication of the ureter and its possible causes

Answer 38

premature bifurcation of the ureteric bud or
formation of two ureteric buds: one ureter may open normally, one may open lower (bladder neck or urethra). Ureter may become enlarged due to obstructed urine flow. There may also be back-flow of urine (vesico-ureteral reflux, VUR) and frequent infections.

Question 39

Describe renal hypoplasia and its possible causes

Answer 39

kidney contains fewer than normal nephrons. May be associated with PAX2, SALL1 mutations

Question 40

Describe renal dysplasia and its possible causes

Answer 40

kidney contains undifferentiated tissue and/or cysts. May be associated with PAX2, SALL1 mutations.

Question 41

Describe accessory renal arteries and its possible causes

Answer 41

transient embryonic renal arteries fail to regress

Question 42

Describe pelvic kidney and its possible causes

Answer 42

failure of kidney to ascend

Question 43

Describe horseshoe kidney and its possible causes

Answer 43

fusion of the inferior poles of the kidneys on each side. Likely cause: abnormality in the kidney capsule. Ascent of kidney is blocked by the inferior mesenteric artery.

Question 44

Describe Vesico-ureteral reflux (VUR)

Answer 44

This disorder refers to the backwards flow of urine from the bladder to the ureters and is one of the more commonly detected congenital anomalies. It is thought to be of complex origin. It may reflect an abnormality in the valve mechanism at the
uretero-bladder junction (primary VUR) or be associated with an obstruction near the ureteropelvic junction (secondary VUR). VUR has been associated with mutations in EYA1 and
ROBO2

Question 45

What is polycystic kidney disease?

Answer 45

PKD is characterized by the formation of fluid filled cysts and kidney enlargement. The timing of cyst formation ranges from the prenatal period through
adulthood. Underlying PKD (as well as other renal cystic diseases) are mutations in proteins localized to non-motile cilia or ciliary basal bodies. These proteins include polycystins 1 and 2 (autosomal dominant PKD) and fibrocystin (autosomal recessive PKD). In kidney epithelia, these solitary cilia appear to function as mechanosensors that detect and transmit signals about fluid flow in tubules to the cell body, a process involving the elicitation of a calcium signal. During growth and development, these cilia may regulate cell polarity,
the cell cycle, and Wnt signaling. How mutations in ciliary proteins lead to cyst formation is
not known but may involve an increase in cell proliferation and a loss of oriented cell division.
Renal cysts are also associated with mutations in HNF-1B, a transcription factor known to
regulate cystic genes like PKD1 and PKD2.

Question 46

Describe urorectal atresia/ fistula and its possible causes

Answer 46

abnormal communication between the rectum and the
urethra, vagina, or bladder. Possible cause: ectopic
positioning and/or size of the cloaca.

Question 47

Describe urachal fistula, sinus, cyst and its possible causes

Answer 47

persistence of part or all of the lumen of the urachus or allantois

Question 48

Describe exstrophy of the bladder and its possible causes

Answer 48

bladder open at anterior body surface, resulting from
defect in the anterior body wall. Possible causes:
insufficient tissue proliferation in anterior body wall,
abnormally large cloacal membrane