Renal System Development 10th week ~12 weeks Dental Human Embryology Course (DENT 5315/OBIO-8024) Brad Martinsen, Ph.D. (marti198@umn.edu) Lecture 5: Topic Assigned Reading Renal Development pages 265-276 Genital Development pages 276-288 The PowerPoint notes pages give a complete review of the reading assignments (Larson’s Human Embryology, 3rd ed.) and what I will say in lecture. You can also refer to the Larson’s Human Embryology Website (http://cna.uc.edu/embryology/) and click on contents for Animations, Updates, Self-tests, and Glossaries of Terms for each Chapter. *Use reading assignments to clarify anything said in lecture or in the notes. Not all detail in the reading assignments will be on the exams. 1 Development of Three Nephric Systems Cervical Nephrotomes & Mesonephroi Upper thoracic region to the third lumbar region I. Development of Three Nephric Systems. Note: The intermediate mesoderm (Fig 10-1) gives rise to the nephric structures of the embryo, to portions of the gonads, and to the male genital duct system. Three sets of nephric structures (cervical nephrotomes, mesonephroi, and metanephroi, the definitive kidneys) develop in craniocaudal succession from the intermediate mesoderm. A. Cervical nephrotomes. 1. Early 4th week five to seven paired cervical segments of intermediate mesoderm give rise to a nephric vesicle/nephrotome (small, hollow ball of epithelium) (Fig 10-2A). 2. Also referred to as the pronephros (Greek for first kidney) because they resemble the functional embryonic pronephroi of some lower vertebrates. 3. The cervical nephrotomes are transient and nonfunctional. They disappear by day 24 or 25. 2 Development of Three Nephric Systems Cervical Nephrotomes & Mesonephroi Renal Corpuscle: Glomerulus & Bowman’s capsule Mesonephric excretory unit: Renal corpuscle & Nephric tubule 6-10weeks-func >10-regress. Mesonephric ducts in females regress and in males they persist to form parts of male genital duct system. 26 Days~22 days Mesonephroi. *Early in the 4th week the nephric (mesonephric) tubules develop within a pair of mesonephroi/mesonephric ridges (elongated swellings of intermediate mesoderm located on either side of the vertebral column) from the upper thoracic region to the third lumbar level (Fig 10-2B-D). Also early in the 4th week the mesonephric ducts (intermediate mesoderm origin) first appear in the form of a pair of solid longitudinal rods (dorsolateral to the developing mesonephric tubules) (Fig 10-2A & Fig 10-3). These rods grow caudally into the lower lumbar region guided by an adhesion gradient between the ectoderm and endoderm. *By day 26, the rods diverge from the intermediate mesoderm and fuse with the ventrolateral walls of the cloaca (Fig 10-2 & Fig 10-4). The region of fusion eventually becomes the posterior wall of the future bladder. During the fusion process the rods also begin to cavitate at their distal ends, forming a lumen. Cavitation progresses cranially forming the mesonephric ducts. At the end of 5th week the cranial regions of the mesonephroi undergo regression, leaving about 20 pairs of tubules occupying the first three lumbar levels. 3 Development of Three Nephric Systems Cervical Nephrotomes & Mesonephroi Renal Corpuscle: Glomerulus & Bowman’s capsule Mesonephric excretory unit: Renal corpuscle & Nephric tubule 6-10weeks-func >10-regress. Mesonephric ducts in females regress and in males they persist to form parts of male genital duct system. 26 Days~22 days Mesonephroi. *The mesonephric tubules differentiate into excretory units that resemble an abbreviated version of the adult nephron (Fig 10-2D). The medial end of the tubule forms the Bowman’s capsule (a cup-shaped sac) which raps around the glomerulus (a knot of capillaries produced on branches of arteries sprouting from the dorsal aorta), forming the renal corpuscle. Each renal corpuscle and nephric tubule is called a mesonephric excretory unit. The lateral tip of each mesonephric tubule fuses with the mesonephric duct, opening a passage from the excretory units to the cloaca. During the 6th to 10th weeks the mesonephric excretory units are functional and produce small amounts of urine. *After 10 weeks the mesonephric excretory units cease to function and then regress. The mesenephric ducts regress in the female, but in the male the mesonephric ducts plus a few modified mesonephric tubules persist and form parts of the male genital duct system (we will talk about in more detail in the next lecture). 4 Development of Three Nephric Systems. Mesonephroi & Metanephroi Regress to the 1st three lumbar levels Sacral Region Mesonephric duct forming Reciprocal induction ~22 days Metanephroi or the definitive kidneys. At the 4th week (day 28) the distal portion of the mesonephric ducts sprout ureteric buds (eventually differentiates into the ureters and the collecting duct system of the kidneys) which induce the metanephroi to form in the intermediate mesoderm of the sacral region (Fig 10-4A). At Day 32 each ureteric bud penetrates the metanephric blastema (a portion of the sacral intermediate mesoderm which appears around the same time) and begins to bifurcate (Fig 10-4B). The metanephros become lobulated in appearance as each ampulla (growing tip of each bifurcated branch) acquires a caplike aggregate of metanephric blastema tissue. The metanephric blastema eventually differentiate into the nephrons (the definitive urine-forming units of the kidneys). During the middle of 6th week the developing metanephros consists of two lobes separated by a sulcus (Fig 10-4C). By the end of the 16th week the metanephros consists of 14 to 16 lobes (Fig 10-4D) and the sulci between the lobes begin to fill in. Note: The ureteric bud and metanephric blastema exert reciprocal inductive effects (classic model of induction). Several hours of direct contact with a ureteric bud ampulla are required to induce nephron differentiation in blastema tissue and the reciprocal inductive signals from the metanephric blastema regulate the orderly bifurcation of the tips of the ureteric buds (discussed in more detail below). If the ureteric bud is abnormal or missing, the kidney does not develop. 5 Sequence of bifurcations. 11 additional generations of bifurcations--> 1-3 mil branches. ~22 days 32nd Week 8 months Collecting duct system (entirely the product of the ureteric bud) of the Metanephroi. Note: The collecting duct system is produced by sequential bifurcation of the ureteric bud. Urine produced by the nephrons flows through the collecting tubules, minor calyces, major calyces, the renal pelvis, and finally, the ureter. This path is called the collecting duct system. Sequence of bifurcations (Fig 10-5 & Fig 10-6A): During the middle of the 4th week when the ureteric bud first contacts the metanephric blastema, its tip expands to form an initial ampulla that will give rise to the renal pelvis. At the 6th week the ureteric bud bifurcates four times, yielding 16 branches which coalesce to form two to four major calyces extending from the renal pelvis. During the 7th week the next four generations of branches also coalesce to form the minor calyces. By 32 weeks 11 additional generations of bifurcation have formed 1 to 3 million branches. These will become the future collecting tubules (collecting ducts) of the kidney (Fig 10-6A). 6 Nephron Development Contains neural crest derived neurons. They play a role in nephron induction. The neurons regulate blood flow and secretory function. 9th week ~22 days Nephron development (Fig 10-6B-F): Each nephron originates as a vesicle within the blastemic cap (surrounding the ampulla of a collecting duct) (Fig 10-6B). The vesicle elongates into a tubule. 7 Nephron Development 10th week 10weeks+-->func: gl. filtrate to urine, but main func to produce amniotic fl. Nephron development (Fig 10-6B-F): *A capillary glomerulus forms near one end of the tubule. The tubule epithelium near the differentiating glomerulus thins and then invaginates to form a Bowman’s capsule (surrounds the glomerulus). Just as in the mesonephros, the renal corpuscle consists of a Bowman’s capsule and the glomerulus. *As the renal corpuscle is developing, the lengthening nephric tubule differentiates into the proximal convoluted tubule, the descending and ascending limbs of the loop of Henle, and the distal convoluted tubule. The definitive nephron with its renal corpuscle is called a metanephric excretory unit. By the 10th week the tips of the distal convoluted tubules connect to the collecting ducts. The metanephroi become functional. Blood plasma from the glomerular capillaries is filtered by the renal corpuscle to produce a dilute glomerular filtrate. The filtrate is concentrated and converted to urine by the convoluted tubules and the loop of Henle. The urine then passes down the collecting system into the ureters and then the bladder. Note: The main function of the fetal kidneys is not to clear waste (mainly handled by the placenta), but instead it supplements the production of amniotic fluid. Thus fetuses with bilateral renal agenesis do not make enough amniotic fluid (oligohydramnios), confining the fetus to an abnormally small amniotic space. 8 Definitive Kidney Architecture Minor calyx Major calyx Pelvis Contains the nephrons. 5th-15th weeks Renal Pyramid (inner medulla) Contains the loops of Henle and collecting ducts . Definitive kidney architecture (Fig 10-7): *During the 5th to 15th weeks the definitive kidney architecture is created. The kidney is divided into an inner medulla (contains the collecting ducts and the loops of Henle) and an outer cortex (contains the nephrons). Each minor calyx drains a tree of collecting ducts within the renal pyramid that converge to form the renal papilla. *The renal pyramids of the kidney are separated by renal column/columns of Bertin (cortical tissue that contains nephrons). Thus the cortical tissue covers the outside of the kidney, as well as projecting towards the pelvis. The nephrons arise from the cortical regions of the primary lobes of the metanephric blastema. Note: Neural crest cells contribute to the function of the Kidney. Neural crest cells invade the metanephroi early in their development. Neural crest cells give rise to the neurons of the kidney that regulate blood flow and secretory function. These neurons are located at the tips of the metanephric tissue caps during nephron induction. Thus these neurons also play a role in the induction of nephron formation. 9 Anomalies during kidney ascent Inferior mesenteric artery ~22 days Kidneys ascend from a sacral to lumbar location. During the 6th to 9th weeks the kidneys ascend to a lumbar site just below the suprarenal glands. They follow a path on either side of the dorsal aorta (Fig 10-8). The mechanism responsible for the relocation of the kidneys is poorly understood. The differential growth of the lumbar and sacral regions of the embryo may play a role. The ascending Kidney is progressively revascularized by a series of arterial sprouts from the dorsal aorta, and the original renal artery in the sacral region disappears (Fig 8-6). Note: The right kidney usually does not rise as high as the left kidney because of the liver on the right side. Anomalies can arise during the ascent of the kidneys: 1. Some of the transient inferior renal arteries occasionally fail to regress. This results in the presence of accessory renal arteries. 2. Also, rarely, a kidney completely fails to ascend, remaining as a pelvic kidney (Fig 10-8C). 3. A U-shaped horseshoe kidney (crosses over the ventral side of the aorta) may also arise if the inferior poles of the two metanephroi fuse during the ascent. This causes the kidney to become caught under the inferior mesenteric artery and subsequently it does not reach its normal site (Fig 10-8D). 10 The remainder of the urinary tract develops from the hingut endoderm Cloacal expansion and partition 4th week Female Male Vestibule of vagina Penile urethra Membranous urethra membranous & prostatic urethra 6th week The remainder of the urinary tract develops form the hindgut endoderm. Cloacal expansion and partition: As mentioned last week, the cloacal expansion of the hindgut is partitioned by the urorectal septum into an anterior primitive urogenital sinus and a posterior rectum (Fig 10-9). The primitive urogenital sinus is continuous superiorly with the allantois (a hindgut diverticulum that extends into the umbilicus) and is bounded inferiorly by the urogenital membrane. The primitive urogential sinus consists of a superior presumtive bladder, pelvic urethrea (the narrow neck), and an inferior definitive urogenital sinus. In males, the pelvic urethra becomes the membranous and prostatic urethra and the definitive urogenital sinus becomes the penile urethra. In females, the pelvic urethra becomes the membranous urethra, and the definitive urogenital sinus becomes the vestibule of the vagina. 11 Exstrophy of the mesonephric ducts and ureteric buds. * * * * 4-6 weeks * * ** -Endoderm grows over trigone -Splanchnopleuric mesoderm associated with the hindgut forms the smooth muscle of the bladder wall. Exstrophy of the mesonephric ducts and ureteric buds (Fig 10-10). *During weeks 4 to 6, via the process of exstropy, the distal portions of the mesonephric ducts and attached ureteric ducts become incorporated into the posterior wall of the presumptive bladder (Fig 10-10). Exstropy refers to the eversion of a hollow organ. During this process the mouths of the mesonephric ducts flare, expand, flatten, and blend into the bladder wall. This process brings the openings of the ureteric buds into the bladder wall, while the opening of the mesonephric duct is carried inferiorly to the level of the pelvic urethra. The mesonephric ducts open into the pelvic urethra just below the neck of the bladder. *The triangular region of exstrophied mesonephric duct, which was incorporated into the posterior bladder wall, forms the trigone of the bladder. Endoderm from the surrounding bladder wall grows over the trigone, but it remains visible in the adult as a smooth triangular region lying between the openings of the ureters laterally and superiorly, and the opening of the pelvic urethra inferiorly. During the 12th week, Splanchnopleuric mesoderm associated with the hindgut forms the smooth muscle of the bladder wall. 12 Ureteric bud or metanephros induction defects Renal agenesis A. Defects in the inductive interaction between the ureteric bud and metanephric blastema may cause renal agenesis. B. Bilateral renal agenesis results in death. Unilateral renal agenesis results in hypertrophic kidney. C. 75% of the cases involving renal agenesis occur in males. D. Bilateral renal agenesis can also result in oligohydramnios, causing Potter’s syndrome (deformed limbs and facial defects. E. Unilateral renal agenesis is usually associated with heart defects and constrictions of the gastrointestinal tract. Ureteric bud or metanephros induction defects. 1. Renal agenesis. a. Defects in the inductive interaction between the ureteric bud and metanephric blastema may cause renal agenesis. b. In the absence of inductive signals from the ureteric bud, the metanephros fails to develop. Infants with bilateral renal agenesis are stillborn or die within a few days after birth. If unilateral renal agenesis occurs the remaining kidney will become hypertrophic to compensate for the missing kidney. c. 75% of the cases involving renal agenesis occur in males. d. Renal agenesis typically causes other congenital defects. Since the kidneys initially contribute to the production of amniotic fluid, bilateral renal agenesis results in oligohydramnios. The insufficient amniotic fluid causes the uterine wall to compress the growing fetus, resulting in Potter’s syndrome (deformed limbs and facial defects—receding chin, low set ears, and parrotbeak nose). e. Unilateral renal agenesis is usually associated with heart defects and constrictions of the gastrointestinal tract. 13 Genital System Development 4-6 weeks ~12 weeks Dental Human Embryology Course (DENT 5315/OBIO-8024) Brad Martinsen, Ph.D. (marti198@umn.edu) Lecture 5: Topic Assigned Reading Renal Development pages 265-276 Genital Development pages 276-288 The PowerPoint notes pages give a complete review of the reading assignments (Larson’s Human Embryology, 3rd ed.) and what I will say in lecture. You can also refer to the Larson’s Human Embryology Website (http://cna.uc.edu/embryology/) and click on contents for Animations, Updates, Self-tests, and Glossaries of Terms for each Chapter. *Use reading assignments to clarify anything said in lecture or in the notes. Not all detail in the reading assignments will be on the exams. 14 The genital and urinary systems develop in close conjunction Primitive sex cord & Paramesonephric duct development (mullerian) 5-6 weeks Third thoracic segment caudally to the posterior wall of the urogenital sinus The genital and urinary systems develop in close conjunction. Review note: During the 5th week, the primordial germ cells migrate from the yolk sac via the dorsal mesentery to the mesenchyme of the posteriror body wall (10th thoracic level) (Fig 10-11A). The primordial germ cells induce cells in the mesonephros and adjacent coelomic epithelium to proliferate and form the genital ridges (Fig 10-11B,C & 10-12). Primitive sex cord development. As mentioned above the primitive sex cords develop from mesonephros cells and coelomic epithelium cells. During the 6th week, these cells invade the region of the presumptive gonads to form the primitive sex cords which completely invest the germ cells (Fig 10-11B). At this point the sex cords have a cortical and medullary regions. After the 6th week these regions pursue different fates in the male and female. Paramesonephric duct (Mullerian) development. During the 6th week, a thickend region of coelomeic epithelium (from the third thoracic segment caudally to the posterior wall of the urogenital sinus) undergoes craniocaudal invagination (Fig 10-11B,C), forming the paramesonephric (mullerian) ducts just lateral to the mesonephric ducts in both male and female embryos. These ducts are enclosed in the basement membrane of the adjacent mesonephric ducts. The caudal tips of the paramesonephric ducts connect with the pelvic urethra (the tips adhere to each other before they connect) just medial to the openings of the right and left mesonephric ducts, while the superior ends form funnelshaped openings into the coelom. 15 Virtually identical male and female genital systems. 6th week At this point the sex cords have both a cortical and medullary region. After the 6th week these regions pursue different fates in the male and female. Virtually identical male and female genital systems (before end of 6th week). *In both sexes, germ cells and sex cords are present in both the cortical and the medullary regions of the presumptive gonads. *Complete mesonephric and paramesonephric ducts are present. *After the end of the 6th week the ambisexual or indifferent phase of genital development ends. *7th week, the male and female systems follow diverging pathways. 16 Basis of sex differentiation Autosomes and Sex Chromosomes 1. There is a total complement of 46 chromosomes, 22 pairs consist of matching homologous chromosomes called autosomes. The 23rd pair are called the sex chromosomes because they determine the sex of the individual. 2. XX individuals are genetically female. XY individuals are genetically male. Subsequent phases of sexual development are controlled by both the sex chromosome genes and by the hormones and factors encoded by the autosomes. 3. The sex-determining region of the Y chromosome (SRY) encodes a transcription factor that controls the choice between the male and female developmental paths. Basis of sex differentiation. Autosomes and Sex Chromosomes: *There is a total complement of 46 chromosomes, 22 pairs consist of matching, homologous chromosomes called autosomes. The remaining two chromosomes are called the sex chromosomes because they determine the sex of the individual. *XX individuals are genetically female and XY individuals are genetically male. Although the pattern of sex chromosomes determines the choice between male and female developmental paths, the subsequent phases of sexual development are controlled by both the sex chromosome genes and by the hormones and factors encoded by the autosomes. 17 Basis of sex differentiation Autosomes and Sex Chromosomes 4. Male development is triggered when SRY is expressed in the sex cords during the indifferent phase. 5. Thus the male pathway is actively induced. *The sex-determining region of the Y chromosome (SRY) encodes a transcription factor that controls the choice between the male and female developmental paths. When SRY is expressed in the sex cord cells (in the indifferent phase) male development is triggered (Fig 10-13). 18 Figure 10-13 Differentiation cascade of male genital system development. 19 Male genital (internal) Development Sertoli cell differentiation in the medullary sex cords ~7th week Male genital (internal) development. Sertoli cell differentiation in the medullary sex cords: 1. The SRY protein causes cells within the medullary region of the primitive sex cords to begin to differentiate into Sertoli cells, while the cells of the cortical sex cords degenerate (Fig 10-13 & 10-14). 2. If SRY is absent the sex cords develop into ovarian follicles. 3. 7th week differentiating Sertoli cells organize to form the testis cords (Fig 10-14). Also, the testis begins to round up, reducing its area of contact with the mesonephros (a feminizing influence). As the testes continue to develop, the degenerating cortical sex cords become separated from the coelomic epithelium by the tunica albuginea (intervening connective tissue). 4. At pubery testosterone surge the testis cords and associated germ cells become canalized and differentiate into the seminiferous tubules. The distal testis cords develop lumina and differentiate into a set of thin-walled ducts called the rete testis. 5. The tubules of the rete testis become connected with 5 to 12 residual mesonephric tubules. The mesonephric ducts become the spermatic ducts or vasa deferentia (vas deferens, singular). 20 Male genital (internal) Development Anti-Mullerian hormone (AMH) secretion by Sertoli cells (reminant of ~8-12th week cranial end of mesonephric duct) Sertoli Cells Ductuli efferentes (reminant of inferior mesonephric tubules) Anti-Mullerian hormone secretion by the pre-Sertoli cells: 1. As the Sertoli cells begin to differentiate in response to the SRY protein, they also begin to secrete anti-Mullerian hormone (AMH) or Mullerian-inhibiting substance (MIS) (glycoprotein). The protein region resembles the transforming growth factor-beta molecule which has been implicated in mesoderm induction and angiogenesis. 2. 8th to 10th weekAMH causes the paramesonephric (mullerian) ducts to regress in the male (Fig 10-13 &10-14). 3. Paramesonephric duct remnants go on to form the appendix testis and utriculus prostaticus in the adult male. In female embryos, the paramesonephric ducts do not regress. 4. 9th week the SRY protein (expressed by the pre-Sertoli cells) also initiates a cascade that induces the differentiation of mesenchymal cells within the genital ridges into testosterone-secreting Leydig cells (in the testis) (Fig 10-13). 5. The Leydig cells (endocrine cells) produce testosterone and this early secretion is regulated by chorionic gonadotropin, secreted by the placenta (later in development the pituitary gonadotropins of the male fetus take over control). 21 Male genital (internal) Development Differentiation of the mesonephric ducts of the male ~10th-12th week Differentiation of the mesonephric ducts of the male: 1. 8th to 12th week, the initial secretion of testosterone stimulates the mesonephric ducts to transform into the spermatic ducts (vasa deferentia) (Fig 10-14). 2. The most cranial end of each mesonephric duct degenerates into the appendix epididymis. 3. The region of the vas deferens adjacent to the presumptive testis differentiates into the convoluted epididymis. 4. During the 9th week, 5 to 12 mesonephric ducts in the region of the epididymis make contact with the cords of the future rete testis. 3rd month, these epigenital mesonephric tubules actually unite with the presumptive rete testis. After uniting the epigenital mesonephric tubules are then called the ductuli efferentes. They provide a pathway from the seminiferous tubules and rete testis tubules to the vas deferens. 5. The mesonephric tubules at the inferior pole of the developing testis (paragenital mesonephric tubules) degenerate into the paradidymis. 22 Male genital (internal) Development Differentiation of the accessory glands of the male urethra ~10th-12th weeks Differentiation of the accessory glands of the male urethra: 1. Three accessory glands of the male genital system all develop near the junction between the mesonephric ducts and the pelvic urethra (Fig 10-15). 2. 10th week, The glandular seminal vesicles sprout from the distal mesonephric duct near their attachment to the pelvic urethra. The portion of the vas defenens (mesonephric duct) distal to each seminal vesicle is called the ejaculatory duct. 3. 10th week, The prostate gland develops from a cluster of endodermal evaginations that bud from the pelvic urethra (induced by dihydrotestoterone). The initial prostatic outgrowths form five solid prostatic cords. By the 11th week, the cords develop a lumen and glandular acini (the surrounding mesenchyme differentiates into the smooth muscle and connective tissue of the prostate) and by the 13th to 15th weeks, as the testosterone concentrations reach a high level, the prostate begins to secrete. 4. 10th week, The paired bulbourethral glands sprout from the urethra (inferior to the prostate). The mesenchyme surrounding the endodermal glandular tissue differentiates into the smooth muscle and connective tissue of the bulbourethral gland. Note: The secretions of the seminal vesicles, prostate, and bulbourethral glands all contribute to the seminal fluid that protects and nourishes the spermatozoa after ejaculation (not absolutely necessary for sperm function). 23 Female genital (internal) development Absence of a Y chromosome Female genital (internal) development. Absence of a Y chromosome: 1. The female sex cord cells do not express SRY protein (they do not contain the Y chromosome/SRY region) and thus do not differentiate into Sertoli cells. As a result, AMH, Leydig cells, and testosterone are not produced. The formation of male structures are not induced, causing the embryo to follow the default pathway of female development (Fig 10-16). 2. In genetic females, the primitive sex cords degenerate and the mesothelium of the genital ridge forms secondary sex cords which invest the primordial germ cells to form the follicle cells of the ovary (Fig 10-16). Review note: The female germ cells enter meiosis, but further development is inhibited by the follicle cells. In males, the pre-Sertoli cells inhibit germ cell development before they enter meiosis. In the female fetus, the germ cells differentiate into oogonia and enter the first meiotic division as primary oocytes. The follicle cells then arrest germ cell development until puberty. The close contact of the genital ridge and mesonephros in females is important for inducing the initial stages of gamete maturation. 24 Female genital (internal) development Absence of AMH in the female embryo Absence of AMH in the female embryo: 1. The mesonephric ducts and mesonephric tubules require testosterone for their development. Thus, in the female, they rapidly disappear, forming two remnants, the epoophoron and paroophoron (found in the mesentery of the ovary). Also, a scattering of tiny remnants called Gartner's cysts cluster near the vagina (Fig 10-16, 10-17C) 2. The paramesonephric ducts develop uninhibited. 25 Female genital (internal) development Absence of AMH in the female embryo 3. The wall of the pelvic urethra (where the growing tips of the paramesonephric ducts adhere) forms a slight thickening called the sinusal tubercle (Fig 10-17A). While fusing with the sinusal tubercle the caudal tips of the paramesonephric ducts fuse in a superior direction (3rd to 5th month), forming the genital canal or uterovaginal canal (superior portion of the vagina and uterus) (Fig 10-17B,C). 4. The superior portions of the unfused paramesonephric ducts become the fallopian tubes (oviducts), and the funnel-shaped superior openings of the paramesonephric ducts become the infundibula of the oviducts (Fig10-16). 5. Also during the 3rd month, the thickening endodermal tissue of the sinusal tubercle in the posterior urethra forms a pair of swellings called the sinuvaginal bulbs (gives rise to the inferior 20 percent of the vagina)(Fig 10-17). 6. The vaginal plate (of unkown origin, occludes the most inferior region of the uterovaginal canal) elongates and becomes canalized by a process of desquamation (cell shedding) to form the inferior vaginal lumen (3rd to 5th month). 26 Female genital (internal) development Absence of AMH in the female embryo 7. While the vaginal plate forms, the lower end of the vagina lengthens caudally until it reaches the posterior wall of the definitive urogenital sinus (4th month) (Fig 10-17C). 8. An endodermal membrane temporarily separates the lumen of the vagina from the cavity of the definitive urogenital sinus (vestibule of the vagina). After the 5th month, this membranes degenerates into the vaginal hymen. 27