GI Organogenesis

Development of the Urogenital System

• The urinary and genital systems are established during embryogenesis and mature during fetal development
• These systems arise from the intermediate mesoderm of the embryo
• Both systems develop in an integrated fashion
• The urinary system functions at birth
• Specific gonads, tracts, and external genitalia are established at birth, but are immature until puberty
• Male and female terms refer to XX or XY chromosomal statuses

The Mature Kidney

• The kidney consists of the renal artery, renal vein, ureter, kidney, medulla, renal pelvis, and cortex

Embryonic Gastrulation

• The intermediate mesoderm contributes to kidney development
• Embryonic gastrulation occurs around day 17-21

Urinary Development

• The urinary system appears in three phases in the human embryo
• Pronephroi appear and disappear by 3.5 weeks, similar to lower vertebrates
• Mesonephroi and associated ducts are functional at 6 weeks and regress after 10 weeks
• Metanephroi form by week 5 and will become the definitive kidney in males and females
• Mesonephric ducts contribute significantly to the male reproductive tract

Mesonephric and Metanephric Context at Week 5

• The mesonephric context includes the remnant of pronephros, mesonephros, developing liver, nephrogenic cord, mesonephric duct, ureteric bud, and metanephrogenic blastema
• The metanephric context includes the superior mesenteric artery, adrenal gland and artery, mesonephric duct and mesonephros

Kidney Development: Reciprocal Inductive Signaling

• Reciprocal inductive signaling directs the ureteric bud and the metanephric blastema to form a functional kidney
• The ureteric bud contributes to the ureters, the renal pelvis, the minor and major calyx structures, and the collecting duct system
• The metanephric blastema contributes to nephron development

Kidney Development: Renal Collecting Systems & Nephrons

• Nephron development has four stages: vesicle (13-19 weeks), S-shaped body (20-24 weeks), capillary loop (25-29 weeks), and mature nephron (infancy)
• Purple represents the ureteric bud contributions of the collecting ducts and the pink represents the metanephric blastema contributions

Gonads & Kidney Location Changes

• Kidneys ascend while the gonads descend, with positional changes to the renal artery supply
• At 5 weeks the location includes the superior mesenteric artery, adrenal gland and artery, and mesonephric duct, mesonephros and inferior mesenteric artery
• At eight weeks they include the adrenal gland, renal artery, kidney, site of previous renal arteries and gonad

Establishment of Openings

• Neural tube, notochord, aorta, mesonephric duct, genital ridge and mesentery all contribute to the function and location

Female Arrangement

• The vaginal canal is derived from the fused ends of the Müllerian ducts
• The vaginal canal descends and fuses, creating the distal vagina

Male Arrangement

• The definitive urogenital sinus develops into the penile urethra
• The prostate and bulbourethral glands are formed from buds
• Seminal vesicles are formed by budding from the ductus deferens (the mesonephric duct)

Ureters and Bladder

• The ureters are transposed from the mesonephric duct to the bladder (trigone region)
• Ureter placement is similar between males and females with positioning occurring between 4-6 weeks
• "Exstrophy" describes the inside-out hollowing of the distal mesonephric duct, bringing the ureters into position

Problems in Kidney Ascent

• Problems associated with kidney ascent include pelvic kidney, and horseshoe kidney

Sex Specification

• Genetic sex (Chr XX, XY dictates
• Gonadal sex (testis vs. ovary) dictates
• Phenotypic sex (internal tract and external genitalia)

Coincidental Kidney Development

• Primordial Germ Cells (PGCs) migrate from the yolk sac to populate a region of the symmetrical mesonephroi
• PGC arrival determines the identity of the genital ridges (GR) through (induction!)
• GR become the bipotential gonads, ready for specification

Bipotential Gonad Development

• Cells from the mesonephros and coelomic epithelium invade the future gonad, surrounding the resident primordial germ cells (PGCs)
• These invading cells will become supporting somatic cells of the future sex-specific gonad
• The organ formation is named the primitive sex cords (paired)
• Another pair of ducts arises alongside the mesonephric ducts, called the paramesonephric ducts, at this indifferent stage
• Mesonephric ducts are the future male Wolffian ducts
• Paramesonephric ducts are the future female Müllerian ducts

Gonad Sex Specification

• Gonad specication is instigated by expression of the SRY transcription factor from Chr Y (XY = testis; XX = ovary)

Male Specification

• Production of Anti-Mullerian Hormone (AMH) from the Sertoli cells of the embryonic testes triggers regression of the female Müllerian ductal system and Leydig cell development
• Testosterone (T) steroid hormone production from the Leydig cells of the embryonic testes triggers secondary sex specification of the male reproductive tract (T)
• Testosterone (T) steroid hormone production from the Leydig cells of the embryonic testes triggers development of external genitalia of the male (dihydrotestosterone, DHT)
• Testes eventually descend into the scrotum (pre or post-birth)

Secondary Sex

• In males, the Wolffian ducts differentiate into the male reproductive tract
• In females, the Müllerian ducts differentiate into the female reproductive tract

Mesonephric Duct

• The mesonephric duct contributes to the efferent ducts of the testis, seminiferous tubules, epididymis and Vas deferens

Female Embryo Developments

• The mesonephric duct regresses in the female
• The base of the Müllerian ducts fuse to form the uterus
• The vaginal canal fuses to the urogenital sinus to form the vaginal opening
• The ovaries are suspended by ligaments near the fimbriae of the fallopian tubes

Male Development

• Normal development of the male external genitalia is dependent upon 5-alpha dihyrotestosterone (DHT) production from testosterone
• Deficiency of 5-alpha-reductase activity leads to DHT deficiency
• This Deficiency of 5-alpha-reductase activity leads to female genitalia development in Chr XY male offspring

Specification of Sex

• The developing penis, urethral folds and genital and scrotal swellings all contribute function
• Sexual specification occurs around 7 weeks

Male Embryo Descent

• Testis descent into the scrotal sac occurs from the time of gonad specification (7 wks) to birth (or soon after)
• Testis descent is facilitated by the shortening gubernaculum, (the genito-inguinal ligament)
• Testes descend under the influence of androgens
• Failure of testis descent is called cryptorchidism

Sex Reversal

• Differences in sexual differentiation occur when signals are insufficient, absent, or in excess
• Absent SRY or downstream signaling in a male embryo leads to female development
• Absent Androgen receptor (steroid hormone receptor) in a male embryo leads to male testes with a female physical appearance
• Insufficient testosterone to DHT conversion in a male embryo leads to male testes and a reproductive tract and female external genitalia
• Excessive androgen production (adrenal gland) in a female embryo leads to a female ovary and male-differentiation

Prevalence

• DSD is a difference/disorder of sexual development (intersex disorders)
• The definition of all DSD is an estimated 1 in 100 prevalence
• It is caused by a single gene disorder or chromosomal abnormalities