Development of Urinary and Reproductive Systems Aleš Hampl November 2024 cloaca Urogenital system – Overall picture Urogenital system – Reminder Urogenital system – Intermediate mesoderm Urogenital system – Early forms of kidneys - Pronephros Recapitulation of three stages of evolution of kidneys in a cranial to caudal sequence: • pronephros • mesonephros • metanephros Nephrotomes Nephric duct Nephrotomes • at about day 22 in cervical part of nephrogenic cord • 7 to 10 groups of epithelial cells • connect to pronephric duct • non-functional • disappear by day 28 pronephros pronephric duct • Nephrogenic cord • Genital ridge Urogenital system – Early forms of kidneys - Mesonephros Mesonephros • caudal continuation of nephrogenic cord • thoracolumbar region • unsegmented intermediate mesoderm • mesonephric ducts (paired) – Wolffian ducts • mesonephric tubuli – open individually into m. duct • 36 to 40 m. tubuli in total (on one side) • some filtration – mesonephric unit • mesonephros is most prominent when metanephros start to shape – active since week 6 til week 10 • then they diasappear fast • mesonephric ducts persist in males Urogenital system – Definitive kidneys - Metanephros Ureteric bud = metanefric diverticulum + Metanephrogenic blastema (mesenchyme) Develop since week 5 Branching and Elongation 14 to 15 x Urogenital system – Definitive kidneys - Metanephros Repeated branching of ureteric bud produces: • ureter • pelvis • calyces (major + minor) • collecting tubuli (1 to 3 millions) Uriniferous tubule = The functional unit of the kidney Ducts of Bellini Area cribrosa Minor calyx Cortex Medulla Nephron Collectingtubule 1 to 1.4 milllions of nephrons in one kidney Nephrons X Collecting tubules Different embryological origin renal corpuscle Urogenital system – Metanephros - Nephrons • arched ampulous endings of ureteric ducts (collecting tubuli) – capping by condensed mesenchyme • part of the cap cells differentiate into nephrogenic vesicle • vesicles elongate • vesicles open to the collecting tubulus on one end • distal from the ducts, the cells of elongating vesicles polarize and form lumen and basal lamina • precursors of endothelia grow into this area - glomerulus • endothelia connect to branches of dorsal aorta – gromerular circulation • production of urine since week 10 5 weeks 6 weeks 8 weeks • ventral outpocketing of the hindgut • sac-like structure (respiration) • in umbilical cord • proximal part – URACHUS – continuos with bladder • URACHUS – transforms to Median umbilical ligament 4.5 weeks Urinary system - Bladder Cloaca = terminal part of the hindgut + allantois Urogenital simus Urorectal septum Primitive rectum Urogenital membrane Anal membrane PerineumCloaca Urinary system – Bladder + Ureters + Urethra • alantois expands - urinary bladder • initially bladder is continuos with alanotois – then obliteration – urachus – median umbilical ligament • caudal portions of mesonepric ducts become absorbed by the bladder wall – separation – ureters + ejaculatory ducts Posterior view Urachus Primitive urethra Ureter Ureter Trigone Ejaculatory duct Genital system Sexual dimorfism – individual can only have one type of genital organs Genetic determination: • Heterogametic (XY) – male • Homogametic (XX) - female Indifferent stage Differentiation into individual sexes 7th weekFertilization = genetic gender established (Barr body) Genital system – 7 weeks at indifferent stage Gonads External genitalia Sertoli cells Leydig cells No MIS No Testosterone Sexual Determination Sexual Differentiation Genital system – Sry gene Sry gene – Sox family TF – on short arm of Y chromosome Default pathway Y chromosome decides XXY – male X0 - female Genital system – Sry gene Pairing of X and Y chromosomes in pseudoautosomal region during meiosis Rare crossing-over causes translocation of SRY to X chromosome: XY females or XX males Genital system – Primordial germ cells PGC - large spherical cells Primordial germ cells (PGC) • first recognizable at day 24 • from epiblast-derived extraembryonic msoderm • few cells among endodermal cells of the yolk sac • they migrate through the dorsal mesentery of the hindgut • migrate towards genital rigdes (plicae genitales) • proliferate during migration • reach genital ridges on week 6 of gestation Males PGC stop dividing Females PGC enter meiosisX decided by somatic cells in the genital ridges Genital system – migration of PGC into gonadal anlagen Genital system – gonadal anlagen Steroidogenic mesoderm along the ventromedial border of the mesonephros caudal region = Genital ridges cranial region = Adrenocortical primordia cells of coelomic epithelium + cells from mesonephric ridge Week 4 – Th6 to S2 cranial + caudal parts involute Week 6 – L3 to L5 become populated by PGC at week 6 Genital system – indifferent gonade (week 6) Gonadal cords Genital system – Differentiation of the testes Late 6th week Cord cells differentiate to Sertoli cells (meiosis-inhibiting factor, anti-mullerian substance, androgen binding factor) Tunica albuginea develops (sets barrier between coelomic epithelium and testis cords) Cord cells form seminiferous tubuli, tubuli recti, and rete testis Rete testis joints ductuli efferentes that are derived from mesonephric ducts (5th to 12th) Week 8 to 18 Leydig cells develop and function in developing testis • from coelomic epithelia and mesonphros • produce testosteron • support development of Wolfian (mesonephric) duct • support development of external genitalia Genital system – Differentiation of the ovaries • PGC concentrate in the cortical region • PGC proliferate (max until week 22) and then enter meiosis – arrest in prophase • Ovarian follicles develop (somatic cell contribution is not understood) • Transient rete ovarii develops in medullary region • Medulla contains connetive tissue and vasculature derived from mesonephros Cortical cords Degenerating medulary cords Genital system – Sexual duct system – Indifferent stage Paramesonephric duct Develops at days 44 to 48 Cranially opens to coelomic cavity Week 7 Wolffian Mullerian Genital system – Sexual duct system – Male Mesonephric ducts (Wolffian) • Ductus epididymis • Ductus deferens • Ductus ejaculatorius • Seminal vesicle Paramesonephric ducts (Mullerian) regresses in week 8 (anti-M hormone) • Appendix testis (cranial part) • Utriculus prostaticus (caudal part) Mesonephros • Ductuli efferentes • Paradidymis (under the testis, nonfunctional) Genital system – Descent of the testes Gubernaculum – originates from caudal portion of genital ridge „Prerequisites + driving forces“ for the descent of testes: • testes enlargement • atrophy of mesonphros – allows for caudal movement • tension of gubernaculum • atrophy of paramesonephric ducts – move to unquinal canal • enlargement of processus vaginalis peritonei (6th month) • increased intraabdominal pressure ? By 26 weeks • the testes have descended retroperitoneally to the deep inguinal rings During 26th week • final descent through the inguinal canals into the scrotum – 2 to 3 days NOTES More than 97% of full-term newborn males have both testes in the scrotum During the first 3 months after birth, most undescended testes descend into the scrotum Spontaneous testicular descent does not occur after the age of one year Genital system – Descent of the testes Processus vaginalis obliterated NORMAL Remaing cyst = Hydrocele ABNORMAL Remanining connection = Risk of hernia ABNORMAL Genital system – Sexual duct system – Female Mesonephric ducts (Wolffian) regresses (absence of testosterone) • Gartners cyst (caudal part) Paramesonephric ducts (Mullerian) • Uterine tubes (oviducts, falopian t.) • Uterus • Vagina Mesonephros (+Mesonephric duct) • Epoophoron (appendix of ovary) • Paraophaoron Genital system – Sexual duct system – Uterus Uterovaginal canal Genital system – Duct system – Uterovaginal channel Dorsal view Lateral view Paramesonephric (Mullerian) ducts fuse to form uterus and upper 1/3 of vagina Genital system – Uterovaginal channel - Anomalies Genital system – External genitalia - Indifferent stage They are derived from a complex mesodermal tissue located around cloaca. Week 8 Week 6 to 8 Genital tubercle – Phallus Urethral (genital) folds – Plicae urogenitales Genital swellings – Tori genitales Orificium urogenitale primitivum demarcated by: HORMONE-INDEPENDENT Genital system – External genitalia - Dimorphism Week 9 to 13 Weeks 12 + 13 are particularly critical = fusing of urethral folds Genital swellings Genital tubercle Genital (urethral) folds Clitoris Labia minora Labia majora Penis Urethra Scrotum MALE FEMALE Genital system – External genitalia - Male Influenced by dihydrotestosterone Influenced by testosterone Genital system – External genitalia - Male Genital tubercle elongates – penis (phallus) Genital swellings enlarge – scrotum Genital folds form the lateral walls of the urethral groove Genital folds form the spongy urethra Ventral epithelium of genital folds – urethra proper Corpora cavernosa develop from mesenchyme Scrotal raphe Urethral raphe Anus Scrotum Genital plate Fused genital folds + Canalized – urethra formed Genital groove Genital system – External genitalia – Urethral orifice • ectodermal ingrowth forms a cellular ectodermal cord Penis body Ectodermal cord Glans penis Spongy urethra Coronary groove Surface ectoderm Spongy urethra Spongy urethra Developing septum External urethral orifice Distal part of spongy urethra Prepuce Glandular part of urethra • the cord grows towards the root of the penis to meet the spongy urethra • the cord canalizes • circular ingrowth of ectoderm occurs at the periphery of the glans penis (week 12) • circular ingrowth breaks down forming prepuce (for some time adherent to the glans penis, hard to retract at birth) Genital system – External genitalia – Male hypospadia Normal midline raphe Raphe off center Genital system – External genitalia - Female urethra and vagina open into vestibule = from urogenital sinus urethra develops from the more cranial part of urogenital sinus – equivalent to prostatic urethra Thank you for your attention ! Questions and comments at: ahampl@med.muni.cz