Embryology

Question 1

The fetal kidneys develop from which of the following embryonic structures? a. Paraxial (somite) mesoderm b. Intermediate mesoderm c. Neural tube d. Lateral mesoderm

Answer 1

B. Intermediate mesoderm

Question 2

At what gestational time point does the metanephros development begin?

a. 2 weeks b. 3 weeks c. 4 weeks d. 5 weeks

Answer 2

C. 4 weeks

Question 3

Which of the following statements is TRUE of the metanephric development?

a. It requires the reciprocal inductive interaction between Müllerian duct and metanephric mesenchyme.
b. The calyces, pelvis, and ureter derive from the differentiation of the metanephric mesenchyme.
c. Older, more differentiated nephrons are located at the periphery of the developing kidney, whereas newer, less differentiated nephrons are found near the juxtamedullary region.
d. In humans, although renal maturation continues postnatally, nephrogenesis is completed by birth

Answer 3

D. IT requires the inductive interaction between the ureteric bud and metanephric mesenchyme. the calyces pelvis and ureter derive from the ureteric bud. Older more differentiated nephros are located at the inner part of the kidney near the juxtamedullary region.

Question 4

The fused lower pole of the horseshoe kidney is trapped by which of the following structures during the ascent?

a. Inferior mesenteric artery
b. Superior mesenteric artery
c. Celiac artery
d. Common iliac artery

Answer 4

A. IMA

Question 5

The homozygous gene disruption (gene knockout) in which of the following molecules does NOT lead to a significant renal maldevelopment in mice?

a. WT-1
b. Pax-2
c. GDNF
d. p53

Answer 5

D. P53

Mutant Wt-1 do not form ureteric buds

PAX-2 gene knockout mice -> no nephric duct, mullerian duct, ureteric bud, metanephric mesenchyme form, animals die 1 day from birth

GDNF knockout mice -> ureteric bud is impaired

Question 6

Which of the following statements is NOT TRUE of GDNF?

a. It is a ligand for the RET receptor tyrosine kinase.
b. GDNF gene knockout mice demonstrate an abnormal renal development.
c. It is expressed in the metanephric mesenchyme but not in the ureteric bud.
d. GDNF arrests the ureteric bud growth in vitro

Answer 6

D. GDNF arrests the ureteric bud growth in vitro

Question 7

The bladder trigone develops from which of the following structures? a. Mesonephric ducts b. Müllerian ducts c. Urogenital sinus d. Metanephric mesenchyme

Answer 7

C Urogenital sinus

Question 8

The urachus involutes to become:

a. verumontanum.
b. the median umbilical ligament.
c. appendix testicle.
d. epoophoron

Answer 8

b. at 12 weeks, the urachus involutes to become the median umbilical ligament

Question 9

Which of the following statements is NOT TRUE of bladder development?

a. The bladder body and trigone is derived from the urogenital sinus and not the terminal portion of the mesonephric ducts.
b. Bladder compliance seems to be low during early gestation, and it gradually increases thereafter.
c. Epithelial-mesenchymal inductive interactions appear to be necessary for proper bladder development.
d. Histologic evidence of smooth muscle differentiation begins near the bladder neck and proceeds toward the bladder dome.

Answer 9

D. at 7-12 weeks, the surrounding connective tissues condense and smooth muscle fibers begin to appear, first at the region of the bladder dome and later proceeding toward the bladder neck

Question 10

The primordial germ cell migration and the formation of the genital ridges begin at which time point during gestation?

a. Third week b. Fifth week c. Seventh week d. Ninth week

Answer 10

B. During 5th 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 adMacent coelomic epithelium to proliferate and form a pair of genital ridges Must medial to the developing mesonephros.

Question 11

Which of the following statements is NOT TRUE of the paramesonephric (müllerian) ducts? a. Both male and female embryos form paramesonephric (müllerian) ducts.

b. In male embryos, the paramesonephric ducts degenerate under the influence of the MIS (müllerian-inhibiting substance) produced by the Leydig cells.
c. In male embryos, the paramesonephric ducts become the appendix testis and the prostatic utricle.
d. In female embryos, the paramesonephric ducts form the female reproductive tract, including fallopian tubes, uterus, and upper vagina

Answer 11

B. In male embryos, the paramesonephric ducts degenerate under the influence of the MIS (müllerian-inhibiting substance) produced by the Leydig cells. A new pair of ducts, called the paramesonephric (müllerian) ducts, begins to form Must lateral to the mesonephric 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 mesonephric ducts. The cranial ends of the paramesonephric ducts form funnel-shaped openings into the coelomic cavity (the future peritoneum). As developing Sertoli cells begin their differentiation in response to the SRY (sexdetermining region of the Y chromosome), they begin to secrete MIS, which causes the paramesonephric (müllerian) ducts to regress rapidly between the 8th and 10th weeks. Small müllerian duct remnants can be detected in the developed male as a small tissue protrusion at the superior pole of the testicle, called the appendix testis, and as a posterior expansion of the prostatic urethra, called the prostatic utricle. In female embryos, MIS is absent, so the müllerian ducts do not regress and instead give rise to fallopian tubes, uterus, and vagina.

Question 12

Which of the following structures in the male reproductive tract develops from the urogenital sinus? a. Vas deferens b. Testis c. Prostate d. Appendix epididymis

Answer 12

B. Prostate. Vas deferens and appendix epididymis all develop from the mesonephric ducts. Testis from the gonadal ridge. The prostate and bulbourethral glands develop from the urogenital sinus.

Question 13

Which of the following statements is NOT TRUE of normal prostate development?

a. It requires the conversion of testosterone into dihydrotestosterone by 5α-reductase. b. It is dependent on epithelial-mesenchymal interactions under the influence of androgens. c. It is first seen at the 10th to 12th week of gestation. d. It requires the effects of MIS.

Answer 13

D. The prostate gland begins to develop during the 10th to 12th week as a cluster of endodermal evaginations budding from the pelvic urethra (derived from the urogenital sinus). These presumptive prostatic outgrowths are induced by the surrounding mesenchyme, and this process depends on the conversion of testosterone into dihydrotestosterone by 5α-reductase. Similar to renal and bladder development, prostatic development depends on mesenchymal-epithelial interactions but under the influence of androgens. There is no evidence that MIS plays a direct role in prostate development.

Question 14

In female embryos, the remnants of the mesonephric ducts persist as the following structures EXCEPT:

a. epoophoron. b. paroophoron. c. hymen. d. Gartner duct cysts

Answer 14

C. hymen

Question 15

Which of the following statements is NOT TRUE of the external genitalia development? a. The appearance of the external genitalia is similar in male and female embryos until the 8th week. b. The external genital appearance of males who are deficient in 5α-reductase is similar to that of females. c. In males, the formation of distal glandular urethra may occur by the fusion of urethral folds proximally and the ingrowth of ectodermal cells distally. d. In females, the urethral folds become the labia majora, and the labioscrotal folds become the labia minora

Answer 15

d. In females, the urethral folds become the labia majora, and the labioscrotal folds become the labia minora. The early development of the external genital organ is similar in both sexes until 8 weeks gestation. Early in the fifth week, a pair of swellings called cloacal folds develops on either side of the cloacal membrane. These folds meet Must 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, then appears on either side of the urogenital folds. In the absence of dihydrotestosterone, the primitive perineum does not lengthen, and the labioscrotal and urethral folds do not fuse across the midline in the female embryo. The phallus bends inferiorly, becoming the clitoris, and the definitive urogenital sinus becomes the vestibule of the vagina. The urethral folds become the labia minora, and the labioscrotal folds become the labia maMora. The external genital organ develops in a similar manner in genetic males who are deficient in 5α-reductase and therefore lack dihydrotestosterone.

Question 16

The testicles descend to the level of internal inguinal ring by which time point during gestation?

a. Sixth week b. Third month c. Sixth month d. Ninth month

Answer 16

B third month

The two stages of testicular descent. (A) Before descent, the developing testis is held in the urogenital ridge by the cranial suspensory ligament (CSL) cranially and the gubernaculum (G) caudally. The adjacent Wolffian duct (WD) forms the epididymis and vas deferens in the male, and the Müllerian duct (MD) forms the uterus and tubes in the female. (B) At the end of the transabdominal phase (*15 weeks or 3rd month), the testis is held near the future inguinal ring by the swelling reaction in the gubernaculum. The skin just beyond the gubernaculum is over the future external inguinal ring, as the scrotum is remote in the perineum of humans. (C) The inguinoscrotal phase requires the gubernaculum to elongate to the scrotum, under control of androgens and calcitonin gene–related peptide (CGRP) released from the genitofemoral nerve (GFN). After migration is complete, the peritoneum of the processus vaginalis (PV) closes and then completely involutes and disappears.

Question 17

Which of the following statements is NOT TRUE of the sexdetermining region of the Y chromosome (SRY)?

a. Its expression triggers the primitive sex cord cells to differentiate into the Sertoli cells. b. Approximately 25% of sex reversal conditions in humans are attributable to SRY mutations. c. It is located on the short arm of the Y chromosome. d. It causes the regression of mesonephric ducts.

Answer 17

D. It causes the regression of mesonephric ducts. When the Ylinked master regulatory gene, called SRY, is expressed in the male, the epithelial cells of the primitive sex cords differentiate into Sertoli cells, and this critical morphogenetic event triggers subsequent testicular development. Analysis of DNA narrowed the location of the SRY to a relatively small region within the short arm of the chromosome. It is now clear that only about 25% of sex reversals in humans can be attributed to disabling mutations of the SRY.

Question 18

The glomerulus, proximal tubule, loop of Henle, and distal tubule are derived from the ___

Answer 18

metanephric mesenchyme

Question 19

The Weigert-Meyer rule states that the most lateral and cephalad ureteric orifice arises ____ and may demonstrate reflux whereas the most medial and caudad orifice drains the ____ and may be associated with a ____

Answer 19

from the lower pole, upper pole, ureterocele.

Question 20

Sertoli cells produce ____, which causes regression of the ___

Answer 20

müllerian-inhibiting substance, müllerian ducts

Question 21

Testosterone is secreted by the ___ and stimulates the ___\_ ducts to form the _

Answer 21

Testosterone is secreted by the Leydig cells and stimulates the wolffian ducts to form the vas deferens and seminal vesicles

Question 22

When ___\_ is deficient, prostatic growth and development is severely compromised.

Answer 22

When 5α-reductase is deficient, prostatic growth and development is severely compromised.

Question 23

In the absence of müllerian-inhibiting substance and androgens, the wolffian ducts ____ and the müllerian ducts give rise to the _____.

Answer 23

In the absence of müllerian-inhibiting substance and androgens, the wolffian ducts degenerate and the müllerian ducts give rise to the fallopian tubes, uterus, and upper two-thirds of the vagina.

Question 24

Boys with spina bifida have a 23% incidence of _____.

Answer 24

Boys with spina bifida have a 23% incidence of cryptorchidism.

Question 25

If the _____ complex is translocated to an X chromosome, an XX female will have male characteristics.

Answer 25

If the _SRY gene_ complex is translocated to an X chromosome, an XX female will have male characteristics.

Question 26

The ______ is important for the normal development and growth of the kidney.

Answer 26

The renin-angiotensin system is important for the normal development and growth of the kidney.

Question 27

Circulating ____ and the conversion of ____ are critical to the normal development of the prostate and male external genitalia.

Answer 27

Circulating androgens and the conversion of testosterone to dihydrotestosterone (DHT) are critical to the normal development of the prostate and male external genitalia.

Question 28

A defect in the ____ may result in hypospadias, cryptorchidism, and ambiguous genitalia (disorders of sex development).

Answer 28

A defect in the _WT1 gen_e may result in hypospadias, cryptorchidism, and ambiguous genitalia (disorders of sex development).

Question 29

Defects in the ____ result in abnormal masculinization of the external genitalia

Answer 29

Defects in the androgen receptor result in abnormal masculinization of the external genitalia

Question 30

\_\_\_\_\_\_ appears to be important for the transit of the testis through the inguinal canal and into the scrotum.

Answer 30

Abdominal pressure appears to be important for the transit of the testis through the inguinal canal and into the scrotum.

Question 31

The embryonic kidneys are, in order of their appearance, the \_\_\_\_, \_\_\_\_\_, \_\_\_\_. The first two kidneys \_\_\_\_\_\_, and the third becomes the \_\_\_\_\_\_\_

Answer 31

The embryonic kidneys are, in order of their appearance, the pronephros, the mesonephros, and the metanephros. The first two kidneys regress in utero, and the third becomes the permanent kidney

Question 32

Müllerian duct remnants in the male include the ___ and \_\_\_\_

Answer 32

Müllerian duct remnants in the male include the prostatic utricle and the appendix testis.

Question 33

Hypospadias can be defined as (3 answers) The most common location of the ectopic urethral meatus is at \_\_\_\_\_\_\_\_

Answer 33

(1) ectopic location of the urethral meatus, (2) incomplete development of the prepuce (dorsal hooded foreskin), and (3) ventral skin deficiency/penile curvature The most common location of the ectopic urethral meatus is at the junction of the penile shaft and glans penis

Question 34

A defect in the __________ leads to severe hypospadia

Answer 34

enzyme 5a-reductase type 2

Question 35

For penile curvatures, the ______ is a nerve free zone amenable to placement of dorsal plication sutures in mild to moderate degrees of curvature, it is also where the _____ is thickest

Answer 35

12 o clock position, tunica albuginea

Question 36

A unique feature of human prostatic development is formation of the verumontanum,\_\_\_\_\_\_. The mesonephric (Wolffian) ducts and the fused Müllerian ducts (MDs; prostatic utricle) join the ___ on the apex of the verumontanum.

Answer 36

A unique feature of human prostatic development is formation of the verumontanum, _a hillock elongated craniocaudally on the dorsal wall of the UGS_ (Fig. 20.17). The mesonephric (Wolffian) ducts and the fused Müllerian ducts (MDs; prostatic utricle) join the _UGE_ on the apex of the verumontanum. Thus, the verumontanum represents an interface between the mesodermal epithelia of the WDs and the prostatic utricle with endodermal UGE

Question 37

Human seminal vesicle appears as a diverticulum of the WD about ____ week of gestation

Answer 37

10-12th

Question 38

Androgen dependent processes in testicular development

Answer 38

1. CSL regression 2. second migratory phase (inguinoscrotal phase)

Question 39

the inguinoscrotal phase of testicular descent requires the gubernaculum to elongate to the scrotum, under control of _____ and _______ released by the \_\_\_\_\_

Answer 39

androgen, Calcitonin gene-related peptide (CGRP), Genitofemoral nerve

Question 40

Androgens differentiate the ambisexual human genital tubercle at ___ gestation into the penis.

Answer 40

Androgens differentiate the ambisexual human genital tubercle at _7 to 8 weeks’_ gestation into the penis.

Question 41

VUR: the mechanism of reflux is a relatively ______ to faciltate the normal unidirectional passage of urine from the kidneys into the bladder. there is a ___ rate of resolution of moderate and low grade VUR

Answer 41

VUR: the mechanism of reflux is a _relatively short intramural ureteral tunnel that lacks sufficient muscle_ to faciltate the normal unidirectional passage of urine from the kidneys into the bladder. High rate of resolution

Question 42

Exstrophy of the bladder is thought to be secondary to failure of ____ to migrate between the ____ of the abdomen and ____ of the cloaca during the fourth week of gestation. This results in absence of the inferior parts of the rectus abdominis muscle, external and internal oblique muscles, and transverse abdominis muscles. The thin epidermis and anterior wall of the bladder rupture, causing an open anterior bladder wall defect

Answer 42

Exstrophy of the bladder is thought to be secondary to failure of _mesechymal_ cells to migrate between the _ectoderm_ of the abdomen and _endoderm_ of the cloaca during the fourth week of gestation. This results in absence of the inferior parts of the rectus abdominis muscle, external and internal oblique muscles, and transverse abdominis muscles. The thin epidermis and anterior wall of the bladder rupture, causing an open anterior bladder wall defect

Question 43

The bladder and urethra develop from the \_\_\_\_, which derives from the ventral portion of the cloaca after it becomes subdivided by the urorectal septum

Answer 43

The bladder and urethra develop from the _endodermal urogenital sinus_, which derives from the ventral portion of the cloaca after it becomes subdivided by the urorectal septum

Question 44

identify the chromosomal defects involved in: autosomal recessive cystic kidney disease autosomal dominant cystic kidney disease tuberous sclerosis congenital nephronopthisis von hippel lindau

Answer 44

autosomal recessive cystic kidney disease- chromosome 6 autosomal dominant cystic kidney disease- chromosome 4 and 16 tuberous sclerosis- chromosome 9 and 16 congenital nephronopthisis- chromosome 2 von hippel lindau- chromosome 3

Question 45

Metanephros The ____ kidney, or the metanephros, initially forms in the ___ region as ureteric buds sprout from the caudal portion of the mesonephric duct and come in contact with condensing (metanephric mesenchyme) at about the __ weeks’ gestation

Answer 45

Metanephros The **definitive kidney**, or the metanephros, initially forms in the **sacral region** as ureteric buds sprout from the caudal portion of the mesonephric duct and come in contact with condensing (metanephric mesenchyme) at about the **4 weeks’ gestation**

Question 46

The ureteric bud elongates **cranially/caudally** into the metanephric mesenchyme ureteric bud, called the a\_ _ \_ _ \_ \_, induces the metanephric mesenchyme to condense and to convert into ____ vesicles . As the ureteric bud divides and branches, each new ampulla acquires a caplike condensation of metanephric mesenchyme that undergoes a _______ transition

Answer 46

The ureteric bud elongates **cranially** into the metanephric mesenchyme and begins to branch dichotomously. The tip of the branching ureteric bud, called the **ampulla**, induces the metanephric mesenchyme to condense and to convert into . As the ureteric bud divides and branches, each **epithelial vesicles**ew ampulla acquires a caplike condensation of metanephric mesenchyme that undergoes a **mesenchymal-toepithelial transition**

Question 47

The metanephric mesenchyme first condenses to form a **\_\_\_\_** layered dense mesenchymal condensate around the ampulla of the advancing ureteric bud. Near the interface of the ampulla and its adjacent ureteric branch, a cluster of cells separates from a mesenchymal condensate and forms an oval mass called a **\_\_\_** that undergoes mesenchymal-to-epithelial conversion. An internal cavity forms within the epithelializing pretubular aggregate, at which point the structure is called the **\_\_\_** (stage I). Cells of the stage I renal vesicles are **\_\_\_** and are stabilized by attachment to a newly formed basement membrane. The renal vesicles elongate to form a **\_\_\_\_** that is in turn converted to an S-shaped body, one end of which establishes connection with the distal tip of a ureteric branch.

Answer 47

The metanephric mesenchyme first condenses to form a **four**- to **five-cell** layered dense mesenchymal condensate around the ampulla of the advancing ureteric bud. Near the interface of the ampulla and its adjacent ureteric branch, a cluster of cells separates from a mesenchymal condensate and forms an oval mass called a **pretubular aggregate** that undergoes mesenchymal-to-epithelial conversion. An internal cavity forms within the epithelializing pretubular aggregate, at which point the structure is called the **epithelial renal vesicle** (stage I). Cells of the stage I renal vesicles are **tall columnar** and are stabilized by attachment to a newly formed basement membrane. The renal vesicles elongate to form a **comma-shaped body** that is in turn converted to an S-shaped body, one end of which establishes connection with the distal tip of a ureteric branch.

Question 48

**Collecting System** The **\_\_\_** of the ureteric bud determines the eventual pelvicalyceal patterns and their corresponding renal lobules . In humans, the first nine branch generations are formed by approximately **\_\_\_\_** gestation. By **\_\_\_\_\_\_**, ureteric bud branching is completed. Thereafter, collecting duct development occurs by **\_\_\_\_\_\_\_**. Between 22 and 24 weeks’ fetal gestation in humans, the **\_\_\_\_ and \_\_\_\_** of the developing kidney are established. The renal cortex, which represents **\_\_\_ of total kidney** volume at birth, becomes organized as a relatively compact, circumferential rim of tissue on the periphery of the kidney. The renal medulla, which represents **\_\_\_** of total kidney volume at birth, has a modified cone shape with a broad base contiguous with cortical tissue. The apex of the cone is formed by convergence of collecting ducts in the inner medulla to form the **\_\_\_** and **\_\_\_** that project into the **\_\_\_\_**. **\_\_ to \_\_\_** minor calyces converge to form _____ major calyces that in turn empty into the renal pelvis. Distinct morphologic differences emerge between collecting ducts located in the medulla compared with those located in the renal cortex. Medullary collecting ducts are organized into elongated linear arrays that converge centrally in a region devoid of glomeruli. In contrast, collecting ducts located in the renal cortex continue to branch and induce metanephric mesenchyme. The **\_\_\_\_\_** of the collecting system, formed from the first five generations of ureteric bud branching, undergo remodeling by increased growth and dilation of these tubules to form the calyces and renal pelvis.

Answer 48

**Collecting System** The **dichotomous branching** of the ureteric bud determines the eventual pelvicalyceal patterns and their corresponding renal lobules . In humans, the first nine branch generations are formed by approximately **15 weeks’** gestation. By **20 to 22 weeks**, ureteric bud branching is completed. Thereafter, collecting duct development occurs by **extension of peripheral branch segments**. Between 22 and 24 weeks’ fetal gestation in humans, the **peripheral (cortical) and central (medullary) domains** of the developing kidney are established. The renal cortex, which represents **70% of total kidney** volume at birth, becomes organized as a relatively compact, circumferential rim of tissue on the periphery of the kidney. The renal medulla, which represents **30%** of total kidney volume at birth, has a modified cone shape with a broad base contiguous with cortical tissue. The apex of the cone is formed by convergence of collecting ducts in the inner medulla to form the **renal pyramids** and **papilla** that project into the **minor calyces**. **Two to three** minor calyces converge to form **three to four** major calyces that in turn empty into the renal pelvis. Distinct morphologic differences emerge between collecting ducts located in the medulla compared with those located in the renal cortex. Medullary collecting ducts are organized into elongated linear arrays that converge centrally in a region devoid of glomeruli. In contrast, collecting ducts located in the renal cortex continue to branch and induce metanephric mesenchyme. The **most central segments** of the collecting system, formed from the first five generations of ureteric bud branching, undergo remodeling by increased growth and dilation of these tubules to form the calyces and renal pelvis.

Question 49

Events are reiterated throughout the growing kidney so that older, more differentiated nephrons are located in the **\_\_\_** near the **\_\_\_\_** and newer, less differentiated nephrons are found at the **\_\_\_**. In humans, although renal maturation continues to take place postnatally, nephrogenesis is essentially complete before birth at around **\_\_\_\_**

Answer 49

Events are reiterated throughout the growing kidney so that older, more differentiated nephrons are located in the **inner part of the kidney** near the **juxtamedullary region** and newer, less differentiated nephrons are found at the **cortex**. In humans, although renal maturation continues to take place postnatally, nephrogenesis is essentially complete before birth at around **32 to 34 weeks’ gestation**

Question 50

Molecular Mechanisms of Kidney Development Formation of renal tubules and the collecting system occurs sequentially and requires dynamic interactions among\_\_\_\_. An inducer tissue, such as ureter or spinal cord, cultured on the opposite side of the filter provided the **\_\_\_**. This ingenious experimental approach has established the kidney as a model system for studying the role of _____ interaction in organogenesis. The development of many other organs, including lung, salivary glands, mammary glands, gonads, prostate, and bladder, also require epithelial-mesenchymal interactions for the controlled differentiation and proliferation of tissues

Answer 50

Molecular Mechanisms of Kidney Development Formation of renal tubules and the collecting system occurs sequentially and requires dynamic interactions among **epithelial, mesenchymal, and stromal cells**. An inducer tissue, such as ureter or spinal cord, cultured on the opposite side of the filter provided the **inductive signa**l. This ingenious experimental approach has established the kidney as a model system for studying the role of **epithelial-mesenchymal** interaction in organogenesis. The development of many other organs, including lung, salivary glands, mammary glands, gonads, prostate, and bladder, also require epithelial-mesenchymal interactions for the controlled differentiation and proliferation of tissues

Question 51

Formation of Nephric Ducts The first recognizable event in renal development is formation of **\_\_\_** within the intermediate mesoderm. The early intermediate mesoderm destined to become nephric ducts is distinguished by expression of the transcription factors ***(3)*** but only **\_\_\_** appears to be absolutely essential for nephric duct formation. PAX2 may be important for maintaining other **\_\_\_\_** in the nephric ducts Available data suggest a model in which few opposing secreted factors from the surrounding tissues cumulatively restrict LIM1 expression to the intermediate mesoderm. LIM1 then activates PAX2 expression to further orchestrate the **\_\_\_\_**

Answer 51

Formation of Nephric Ducts The first recognizable event in renal development is formation of **pronephric duct**s within the intermediate mesoderm. 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. PAX2 may be important for maintaining other **marker gene expression** in the nephric ducts Available data suggest a model in which few opposing secreted factors from the surrounding tissues cumulatively restrict LIM1 expression to the intermediate mesoderm. LIM1 then activates PAX2 expression to further orchestrate the **formation of nephric ducts.**

Question 52

Ureteric Bud Outgrowth Into Metanephric Mesenchyme The outgrowth of the ureteric bud from the **\_\_\_** and its invasion into the condensing blastema of metanephric mesenchyme is a crucial initiating event in the development of the adult kidney (metanephros). Many candidate genes have been identified to play a critical role in this process. In particular, several lines of evidence have revealed a crucial role of the **-\_\_-** in the ureteric bud outgrowth. **\_\_\_\_** is a secreted peptide expressed in the metanephric mesenchyme that activates the **\_\_\_**, which is expressed in the mesonephric duct. GDNF activation of RET requires the glycosylphosphatidylinositol **\_\_\_**, which is expressed in both metanephric mesenchyme and the mesonephric duct. Gene knockout mutations in Ret, GDNF and GFRα1 (Cacalano et al., 1998) **\_\_\_\_** ureteric bud outgrowth.

Answer 52

Ureteric Bud Outgrowth Into Metanephric Mesenchyme The outgrowth of the ureteric bud from the **mesonephric duct** and its invasion into the condensing blastema of metanephric mesenchyme is a crucial initiating event in the development of the adult kidney (metanephros). Many candidate genes have been identified to play a critical role in this process. In particular, several lines of evidence have revealed a crucial role of the **RET-GDNF-GFRα1 pathway** in the ureteric bud outgrowth. **Glial cell line–derived neurotrophic factor (GDNF)** is a secreted peptide expressed in the metanephric mesenchyme that activates the **RET receptor**, which is expressed in the mesonephric duct. GDNF activation of RET requires the glycosylphosphatidylinositol **(GPI)-linked protein GFRα1**, which is expressed in both metanephric mesenchyme and the mesonephric duct. Gene knockout mutations in Ret, GDNF and GFRα1 (Cacalano et al., 1998) **induce** ureteric bud outgrowth.

Question 53

Homozygous mutation of transcription factor Eya1 causes **\_\_\_\_** and a resultant lack of GDNF expression in metanephric mesenchyme, suggesting that Eya1 regulates GDNF expression. In humans, haploinsufficiency of Eya1 results in a dominantly inherited disorder called **\_\_\_\_ syndrome**, which involves kidney and urinary tract anomalies .

Answer 53

Homozygous mutation of transcription factor Eya1 causes **failure of ureteric bud outgrowth** and a resultant lack of GDNF expression in metanephric mesenchyme, suggesting that Eya1 regulates GDNF expression. In humans, haploinsufficiency of Eya1 results in a dominantly inherited disorder called **branchio-oto-renal syndrome**, which involves kidney and urinary tract anomalies

Question 54

PAX2, a paired-box–type transcription factor that is mutated in humans with **\_\_\_** syndrome, is a **\_\_\_\_** regulator of ureteric bud branching. During renal development, Pax2 is expressed in the **(3)** induced by ureteric bud branch tips. Mice with a Pax2 mutation exhibit **\_\_\_\_** ureteric bud branching and renal hypoplasia . Ureteric bud branching is also positively regulated by **\_\_\_** signaling, which promote **\_\_\_\_**. Rarα and Rarβ2 are expressed in stromal cells surrounding Ret-expressing ureteric bud branch tips. Mice deficient in these receptors exhibit a ecreased number of ureteric bud branches and diminished expression of Ret

Answer 54

PAX2, a paired-box–type transcription factor that is mutated in humans with **renal coloboma** syndrome, is a **positive** regulator of ureteric bud branching. During renal development, Pax2 is expressed in the **mesonephric duct, ureteric bud, and metanephric mesenchymal aggregates** induced by ureteric bud branch tips. Mice with a Pax2 mutation exhibit **decreased** ureteric bud branching and renal hypoplasia . Ureteric bud branching is also positively regulated by **vitamin A and its retinoic acid receptor** signaling, which promote **Ret expression**. Rarα and Rarβ2 are expressed in stromal cells surrounding Ret-expressing ureteric bud branch tips. Mice deficient in these receptors exhibit a ecreased number of ureteric bud branches and diminished expression of Ret

Question 55

**REnal Tubulogenesis** Classic tissue recombination experiments focused almost exclusively on the relationship between metanephric mesenchymal cells and ureteric bud epithelial cells. It is now clear that at least three cell types are involved in the control of renal development: the **(3)** cells. Once induced by the ureteric bud, the metanephric mesenchyme patterns itself into at least two different cell populations, a ___ one and a ___ one. The tubular cell population is thought to derive from **\_\_\_\_** in direct contact with the ureteric bud ampulla , whereas the **\_\_\_\_** population surrounds the tubular cells. Once the mesenchyme has been patterned, these cells in the tubular zone undergo morphogenesis to become **\_\_\_**. There is evidence that this process is dependent not only on signals from the **\_\_\_** but also on signals from the **\_\_\_\_**. One of these autocrine signals may be **\_\_\_\_**, whose expression is induced in cells of the tubular zone after interaction with the ureteric bud. In **\_\_\_\_** knockout mice, the ureteric bud forms and invades the metanephric mesenchyme, but subsequent development of epithelial tubules is ____ . This suggests that two signals are essential for renal tubule formation—initial ureteric bud–derived signals activating Wnt4 expression in the metanephric mesenchyme and Wnt4 itself as a mesenchymal autocrine signal.

Answer 55

Tubulogenesis Classic tissue recombination experiments focused almost exclusively on the relationship between metanephric mesenchymal cells and ureteric bud epithelial cells. It is now clear that at least three cell types are involved in the control of renal development: the **ureteric bud tip cells, the condensed metanephrogenic mesenchymal cells, and the stromal or interstitial mesenchymal** cells. Once induced by the ureteric bud, the metanephric mesenchyme patterns itself into at least two different cell populations, a tubular one and a stromal one. The tubular cell population is thought to derive from **mesenchymal cells** in direct contact with the ureteric bud ampulla (Stark et al., 1994; Torres et al., 1995; Vainio et al., 1989), whereas the **stromal cell** population surrounds the tubular cells (Hatini et al., 1996). Once the mesenchyme has been patterned, these cells in the tubular zone undergo morphogenesis to become **renal tubular epithelial cells**. There is evidence that this process is dependent not only on signals from the **ureteric bud** but also on signals from the **mesenchyme itself**. One of these autocrine signals may be **Wnt4**, whose expression is induced in cells of the tubular zone after interaction with the ureteric bud. In **Wnt4 gene** knockout mice, the ureteric bud forms and invades the metanephric mesenchyme, but subsequent development of epithelial tubules is abolished (Stark et al., 1994). This suggests that two signals are essential for renal tubule formation—initial ureteric bud–derived signals activating Wnt4 expression in the metanephric mesenchyme and Wnt4 itself as a mesenchymal autocrine signal.

Question 56

Tubulogenesis Signals from the stromal cell population also contribute to tubule formation, because tubulogenesis is perturbed in **\_\_\_\_** knockout mice. The discovery that Wnt4 acts as a downstream signal during the induction cascade leading to **\_\_\_** leads to the question regarding the nature of the initial ureteric bud–derived signals. In vitro data suggest a role for **\_\_\_** and other uncharacterized factors secreted by the ureteric bud. Localization of **\_\_\_\_** to the ureteric bud tips is reinforced by both **\_\_\_\_** emanating from surrounding stromal cells. For example, **\_\_\_\_** are expressed in the stromal cells and are required for stromal cell–mediated signaling to maintain high levels of RET expression in the bud tips . Consistent with the role of retinoic acid receptors in maintaining RET expression in the dividing ureteric bud, rats with vitamin A deficiency have **\_\_\_\_**.

Answer 56

Tubulogenesis Signals from the stromal cell population also contribute to tubule formation, because tubulogenesis is perturbed in **Bf2 gene** knockout mice. The discovery that Wnt4 acts as a downstream signal during the induction cascade leading to **renal tubulogenesis** leads to the question regarding the nature of the initial ureteric bud–derived signals. In vitro data suggest a role for **FGF2** and other uncharacterized factors secreted by the ureteric bud. Localization of **RET protein** to the ureteric bud tips is reinforced by both **GDNF and signals** emanating from surrounding stromal cells. For example, **retinoic acid receptors** are expressed in the stromal cells and are required for stromal cell–mediated signaling to maintain high levels of RET expression in the bud tips . Consistent with the role of retinoic acid receptors in maintaining RET expression in the dividing ureteric bud, rats with vitamin A deficiency have **smaller kidneys and fewer nephrons**.

Question 57

The cellular cross-talk among stromal, mesenchymal, and ureteric bud cells is further highlighted by gain- and loss-of-function experiments involving **\_\_\_ and \_\_**. **\_\_\_** mutant mice have fewer branch points and correspondingly fewer nephrons, whereas ectopic **\_\_\_** in organ culture can stimulate branching . **\_\_\_ and \_\_\_** affect elongation of the ureteric bud stalk before the branch-point decision is made . Null mutations in **\_\_\_** are associated with even more severe phenotypic anomalies, exhibiting limited ureteric bud branching morphogenesis and complete renal developmental arrest. Yet it is difficult to assess how FGFs and BMPs exert their collective effects on branching given the interplay among all the cell types present in the early kidney

Answer 57

The cellular cross-talk among stromal, mesenchymal, and ureteric bud cells is further highlighted by gain- and loss-of-function experiments involving **FGFs and BMPs**. **Fgf7-null** mutant mice have fewer branch points and correspondingly fewer nephrons, whereas ectopic **FGF7** in organ culture can stimulate branching . **FGF1 and FGF10** affect elongation of the ureteric bud stalk before the branch-point decision is made . Null mutations in **Bmp7** are associated with even more severe phenotypic anomalies, exhibiting limited ureteric bud branching morphogenesis and complete renal developmental arrest.

Question 58

**Mesenchymal-Epithelial Conversion** The inductive signals emanating from the ureteric bud promote **\_\_\_\_** of the metanephric mesenchymal cells around the ureteric bud tips and subsequent tubulogenesis . Mice with null mutations of **\_\_\_ or \_\_\_** fail to exhibit ureteric bud outgrowth, and in both cases the metanephric mesenchyme does not respond to induction even when recombined with strong inducers in vitro. The establishment of glomerular versus tubular cell fates is dependent on **\_\_\_** between Wt1 and Pax2. During early kidney development, the expression domain of Pax2 is complementary to that of Wt1 in **\_\_\_**. Wt1 expression is restricted to **\_\_\_\_\_** ,whereas Pax2 expression is restricted to the portion that gives rise to **\_\_\_\_** precursors of the **\_\_\_\_** segments and later repressed in differentiated **\_\_\_**. Evidence in support of Wnt proteins as ___ inducers has been gained from in vitro induction assays using Wnt-expressing cell lines. Of the Wnt mutants examined to date, only **\_\_\_**, which is expressed in the mesenchyme and not the ureteric bud, is crucial for propagation of the inductive signals. Although Wnt4 mutant mesenchyme is able to aggregate in response to ureteric bud contact, these mutant aggregates do not form **\_\_\_** epithelia.

Answer 58

**Mesenchymal-Epithelial Conversion** The inductive signals emanating from the ureteric bud promote **condensation** of the metanephric mesenchymal cells around the ureteric bud tips and subsequent tubulogenesis . Mice with null mutations of **Pax2 or Wt1** fail to exhibit ureteric bud outgrowth, and in both cases the metanephric mesenchyme does not respond to induction even when recombined with strong inducers in vitro. The establishment of glomerular versus tubular cell fates is dependent on **negative feedback** between Wt1 and Pax2. During early kidney development, the expression domain of Pax2 is complementary to that of Wt1 in **S-shaped bodies**. Wt1 expression is restricted to **glomerular epithelial precursors** ,whereas Pax2 expression is restricted to the portion that gives rise to **tubular epithelial** precursors of the **proximal and distal nephron** segments and later repressed in differentiated **tubular epithelium**. Evidence in support of Wnt proteins as **mesenchyme** inducers has been gained from in vitro induction assays using Wnt-expressing cell lines. Of the Wnt mutants examined to date, only **Wnt4**, which is expressed in the mesenchyme and not the ureteric bud, is crucial for propagation of the inductive signals. Although Wnt4 mutant mesenchyme is able to aggregate in response to ureteric bud contact, these mutant aggregates do not form **polarized** epithelia

Question 59

Renal Vascular Development There is evidence, however, that the renal vessels may originate in situ, within the ___ from vascular progenitor cells. Using antibodies to **\_\_\_**, a vascular endothelial growth factor (VEGF) receptor present in angioblasts and mature endothelial cells, it was demonstrated that endothelial cell precursors were already present in the prevascular rodent metanephric mesenchyme before any vessels were discernible from a morphologic standpoint. When embryonic kidneys are cultured at the usual atmospheric oxygen concentration, **\_\_\_\_**. However, if the explants are cultured in a hypoxic atmosphere containing 5% oxygen, capillary sprouts develop within and outside the glomeruli, an effect that is inhibited by ___ .

Answer 59

Renal Vascular Development There is evidence, however, that the renal vessels may originate in situ, within the **embryonic metanephric mesenchyme** from vascular progenitor cells. Using antibodies to **Flk-1**, a vascular endothelial growth factor (VEGF) receptor present in angioblasts and mature endothelial cells, it was demonstrated that endothelial cell precursors were already present in the prevascular rodent metanephric mesenchyme before any vessels were discernible from a morphologic standpoint. When embryonic kidneys are cultured at the usual atmospheric oxygen concentration, **vessels do not develop**. However, if the explants are cultured in a hypoxic atmosphere containing 5% oxygen, capillary sprouts develop within and outside the glomeruli, an effect that is inhibited by **anti-VEGF antibodies**. Depending on the developmental potential of the cells involved, both angiogenesis and vasculogenesis may play a role in the development of renal vasculature

Question 60

**Clinical Correlation: Vascular Anomalies** As the kidneys migrate from their origin in the pelvis cranially into the upper lumbar region, they are vascularized by a succession of **\_\_\_\_** that arise at progressively higher levels. These arteries do not elongate to follow the ascending kidneys but instead degenerate and are replaced by successive new arteries. The final pair of arteries forms in the upper lumbar region and becomes the **\_\_\_\_**. Occasionally, a more inferior pair of arteries persists as **\_\_\_\_**. These lower-pole arteries cross ventral to the ureter and can cause intermittent **\_\_\_\_\_\_** requiring repositioning of the ureter behind the accessory lower-pole renal artery. The common variation in blood supply to the kidney is a reflection of the continually changing embryonic renal vasculature. This is reflected in that **\_\_\_** of adult kidneys have two or more renal arteries

Answer 60

**Clinical Correlation: Vascular Anomalies** As the kidneys migrate from their origin in the pelvis cranially into the upper lumbar region, they are vascularized by a succession of **transient aortic sprouts** that arise at progressively higher levels. These arteries do not elongate to follow the ascending kidneys but instead degenerate and are replaced by successive new arteries. The final pair of arteries forms in the upper lumbar region and becomes the **definitive renal arteries**. Occasionally, a more inferior pair of arteries persists as **accessory lower-pole arteries**. These lower-pole arteries cross ventral to the ureter and can cause intermittent **ureteropelvic junction obstruction** requiring repositioning of the ureter behind the accessory lower-pole renal artery. The common variation in blood supply to the kidney is a reflection of the continually changing embryonic renal vasculature. This is reflected in that **25%** of adult kidneys have two or more renal arteries

Question 61

**Clinical Correlation: Ascent Anomalies** Between the **\_\_\_**, the kidneys ascend to the upper lumbar region just below the adrenal glands. The precise mechanism responsible for renal ascent is not known, but it is speculated that differential growth of the lumbar and sacral regions of the embryo plays a major role. When the kidney fails to ascend properly, its location becomes ectopic. If its ascent fails completely, it remains as a **\_\_\_**. The **\_\_\_\_** of the kidneys may also fuse, forming a horseshoe kidney **\_\_\_\_\_ incidence** that crosses ___ to the aorta. During ascent, the fused lower pole is arrested by the **\_\_\_\_** and thus does not reach its normal site. Typically, the horseshoe kidney produces no symptoms but can be associated with a **slight increase in ___ and \_\_\_**. Rarely, the kidney fuses to the contralateral one and ascends to the opposite side, resulting in a **\_\_\_\_.**

Answer 61

**Clinical Correlation: Ascent Anomalies** Between the **sixth and ninth weeks**, the kidneys ascend to the upper lumbar region just below the adrenal glands. The precise mechanism responsible for renal ascent is not known, but it is speculated that differential growth of the lumbar and sacral regions of the embryo plays a major role. When the kidney fails to ascend properly, its location becomes ectopic. If its ascent fails completely, it remains as a **pelvic kidney**. The **inferior poles** of the kidneys may also fuse, forming a horseshoe kidney **(incidence ~1 : 500**) that crosses **ventral** to the aorta. During ascent, the fused lower pole is arrested by the **inferior mesenteric artery** and thus does not reach its normal site. Typically, the horseshoe kidney produces no symptoms but can be associated with a **slight increase in ureteropelvicjunction obstruction and renal calculi**. Rarely, the kidney fuses to the contralateral one and ascends to the opposite side, resulting in a **cross-fused ectopy.**

Question 62

**Clinical Correlation: Cystic Renal Disease** Autosomal recessive polycystic kidney disease occurs in approximately 1 : 20,000 live births. Most cases have a mutation in the **\_\_** gene that results in microscopic cystic kidney disease and congenital hepatic fibrosis. The severe renal disease often results in **\_\_\_\_** causing \_\_\_. In patients with nonlethal pulmonary status, early renal replacement by peritoneal dialysis and subsequent renal/liver transplantation has allowed survival (Chandar et al., 2015).

Answer 62

**Clinical Correlation: Cystic Renal Disease** Autosomal recessive polycystic kidney disease occurs in approximately 1 : 20,000 live births. Most cases have a mutation in the **PKHD1** gene that results in microscopic cystic kidney disease and congenital hepatic fibrosis. The severe renal disease often results in **pulmonary hypoplasia** causing **neonatal death**. In patients with nonlethal pulmonary status, early renal replacement by peritoneal dialysis and subsequent renal/liver transplantation has allowed survival (Chandar et al., 2015).

Question 63

**Clinical Correlation: Multicystic Dysplastic Kidneys** Multicystic dysplastic kidneys occur in approximately 1 : 2400 to 1 : 4800 newborns. In the majority of cases, this is a unilateral process with the nonaffected kidney exhibiting **\_\_\_\_**. Multicystic dysplastic kidneys are characterized by **\_\_\_** without recognizable glomeruli. The malformed tissue consists of noncommunicating cysts of various sizes with **\_\_\_\_**. The etiology is not known but is thought to be related to **\_\_\_\_** between the ureteral bud and the metanephric blastema. Treatment consist of documenting that the contralateral kidney remains healthy and **\_\_\_** for the lack of function of the multicystic dysplastic kidney. The multicystic dysplastic kidney will **\_\_\_** and is not at risk for **\_\_\_\_.** ____ may be a nonrecognizable form of multicystic dysplastic kidney in which the involution occurs early in gestation before the abnormal renal development can be detected by prenatal sonogram.

Answer 63

**Clinical Correlation: Multicystic Dysplastic Kidneys** Multicystic dysplastic kidneys occur in approximately 1 : 2400 to 1 : 4800 newborns. In the majority of cases, this is a unilateral process with the nonaffected kidney exhibiting **compensatory hypertrophy** (Gaither et al., 2018). Multicystic dysplastic kidneys are characterized by **nonfunctional renal tissue** without recognizable glomeruli. The malformed tissue consists of noncommunicating cysts of various sizes with **dysplastic tubular epithelium** (Rojas et al., 2011). The etiology is not known but is thought to be related to **abnormal signaling** between the ureteral bud and the metanephric blastema. Treatment consist of documenting that the contralateral kidney remains healthy and **compensates** for the lack of function of the multicystic dysplastic kidney. The multicystic dysplastic kidney will t**ypically involute over time** and is not at risk for **cancer or hypertension**. **Renal agenesis** may be a nonrecognizable form of multicystic dysplastic kidney in which the involution occurs early in gestation before the abnormal renal development can be detected by prenatal sonogram.