ORGANOGENESIS OF THE UROGENITAL SYSTEMS. M.A.KAI-KAI

Learning Objectives This lecture will discuss: The derivatives of the intermediate mesoderm Incuding; the formation of the nephric systems the formation of the genital ducts the formation of the gonads the formation of the external urinary and genital organs

Overview of organogenesis of the urogenital organs Urinary and reproductive systems are closely associated in topography,function and development. Two systems have common origin from the urogenital ridge(UGR) and have homologous structures. Internal genital duct system is derived from the foetal urinary system. Malformation of one system affects the other. The UGR is longitudinal swelling in dorsolateral side of the abdomen UGR--> formed mostly from --non-segmented intermediate mesoderm Lateral UGR(nephrogenic plate) forms urinary organs and internal genital ducts. Ventromedial UGR is genital ridge, forms gonads. Cr. V D Ca. Gonad Mesonephros (nephrogenic Plate) (genital ridge) Mesonephric Duct Paramesonephric duct The Urogenital ridge

Reptiles,birds,mammals The nephrogenic plate differentiates in a rostral to caudal direction and bilaterally. The three nephric systems appear in recapitulating sequence during development. Progression in time Vestigial Pronephros (functional in lower fishes) Developing Gastrointestinal tract Mesonephric Tubules(higher fishes and Amphibians) Segmented intermediate mesoderm (mesonephros) Unsegmented intermediate mesoderm (mesonephros) Mesonephric duct Ureteric bud Unsegmented intermediate mesoderm (metanephros) Reptiles,birds,mammals

Sequence of development of the metanephros(1) Metanephrogenic mass Mesonephric duct Metanephros develops at somites 26-28 from 2 precursors --> ureteric bud(UB) and metanephrogenic mass [A,(MM)] Formation UB and MM is by reciprocal inductive interactions between the tissues. The diverticulum forms caudal of the existing mesonephric duct and grows and into the MM at the nephrogenic plate UB forms the duct system MM forms nephrons The ureteric bud branches as it grows towards the metanephrogenic mass(B) A Urachus Bladder Int.mesoderm Ureteric bud Collecting ducts Cr D Ca. Metanephros Ureter B

Morphogenesis of the ureteric bud(2) The ureteric bud forms the duct system The metanephrogenic mass forms the nephrons by nephrogenesis. Nephrogenesis and differentiation of the ureteric bud are co-ordinated Dichotomous branching pattern of the ureteric bud is species specific. Branching of simple unilobar/ unipyramidal kidneys(dog,horse) the proximal end dilates into a renal pelvis with collecting ducts at the tip In multipyramidal kidneys(ox) ureter bifurcates into 2 major calyces and several minor calyces then collecting ducts Kidney of dog cortex medulla renal pelvis collecting duct ureter collecting duct cortex minor calyx ureter medulla major calyx Kidney of ox

Development of the metanephros(3) Stages in nephrogenesis. Solid cluster of metanephrogenic mass forms(A) and hollows into a renal vesicle(B) with epithelial lining this elongates into metanephric tubules (C). Proliferation,elongation of the MM dependent upon reciprocal tissue interactions using several molecular signalstubules grow and form parts of nephrons. Collecting duct Fusion Distal Ureteric bud by

Nephrogenesis. Formation of glomerulus Fusion, elongation of nephric tubules and association with capillary, to form of glomerulus Proximal tube forms PCT, end dilates and invaginates to form the Bowman's capsule(D) Distal tube forms DCT and fuses with the collecting tubule. BC invaded by the glomerulusforms renal corpuscle (RC). Large numbers of nephrons form Interstitial connective tissue forms between nephrons and thick fibrous capsule surrounds the kidney. Nephrogenesis ceases at birth, continues for 1-3 wks in the dog and pig Bowman’s capsule Arteriole Collecting tubule Capillary Proximal tubule of nephron Fusion Distal tubule of nephron Collecting duct Arteriole Endothelial layer Fused basal lamina Glomerulus Podocyte layer Structure of renal corpuscle (Bowman’s capsule and glomerulus

Glial derived neurotrophic factor(GDNF) regulates growth and branching of ureteric bud Wild type mouse has normal branching of ureteric bud B. GDNF gene knock out mouse no branching

Gonadogenesis(1). The bipotential gonad Gonadogenesis occurs at the genital ridge initiated by 2 simultaneous events:- (i).Formation of gonadal cords Epithelium from degenerate mesonephric nephrons invade genital ridge.And form network of epithelial cords (ii).Migration of primordial germ cells. PGC are endodermal cells, migrate from the yolk sac into the bipotential gonad.The gonad has a central medulla and a peripheral cortex, surrounded by coelomic epithelium. Mesonephric/Wolffian duct PGC arrive at the genital ridge at 21 days cat and proliferate. Epithelial incorporate PGC, forming gonadal cords. Gonadal differentiation begins. Arteriole Dorsal aorta Glomerulus Dorsal mesentery Mesonephric tubule Genital ridge Migratiing PGC

SEX DETERMINATION Red arrows shows gene regulation Mullerian/ Paramesonephric duct DAX Wnt 4 Ovary Oestrogen Female genital ducts Gonadal ridge Bipotential gonad SRY Testis Anti-Mullerian hormone (Sertoli cells) Primary sex determination at fertilisation (i). genetic sex: XY, XX (ii).Y chromosomes encodes testis-determining factorSRYgonadogenesis secretion of foetal hormones by interstitial cells[(Sertoli and Leydig(M),theca cells(F)] secondary sex(phenotypic sex) Regression of Mullerian duct Testosterone (Leydig cells) Differentiation of Wolffian duct into Male genital ducts Descent of testis

Definitive gonads:Testis Wolffian duct Rete testis A Definitive gonads:Testis Dorsal mesentery Germ cells and Sertoli cells concentrate in the testicular cords The cortex develops a thick fibrous capsule Testicular cords form loops (seminiferous tubules) and interconnect with mesonephric tubules to form efferent ducts Testicular cords Mullerian duct Fibrous capsule Interstitium Efferent ducts Wolffian duct B Mullerian duct Seminiferous tubules Gilbert 2006

In the absence of the Y chromosome in primordial germ cells. Wolffian duct A Ovary formation. Dorsal mesentery In the absence of the Y chromosome in primordial germ cells. Ovarian cords concentrate in the cortex The medulla degenerates. The remnants form the vascular, lymphatic and nervous tissues. Meiosis begins and is arrested at diplotene of prophase I when epithelia surround germ cells forming primordial follicles. Interstitium Mullerian duct Ovarian cords Germinal epithelium Oocyte B Primordial follicle Wolffian duct Gilbert 2006)

Formation of the urogenital sinus(UGS) Schematic diagram of lateral view.15days dog Cloaca is common opening for the urinary and digestive systems and bounded caudally by the the cloacal membrane. Formation of the UGS begins with division of the cloaca by the mesodermal urorectal septum separating cloaca into dorsal anus and ventral urogenital parts, bounded by anal and urogenital membranes. Membranes degenerate forming the anal and urogenital orifice A Mesonephric duct Metanephrogenic mass Mesonephros Ureteric bud Hindgut Hindgut Hindgut Urogenital sinus Anus Cr Cloaca Urorectal septum V D Urachus Ca.

Differentiation of female and male ducts The UGS opens into the allantoic cavity via the urachus It divides into a cranial pelvic region and caudal phallic region. --The cranial UGS expands into the bladder and urethra in both sexes. --The caudal UGS forms penile urethra in male and vagina in female. In female(B)Paramesonephric ducts form female genital ducts, fuse caudally to form uterus and vagina In male(C) the Wolffian/mesonephric ducts form epididymis and ductus deferens. And Mullerian/paramesonephric duct regresses. Mesonephric/ Wolffian duct Paramesonephric/ Mullerian duct A Hindgut Bipotential gonad Ureter Cloaca Urachus Bladder Indifferent Urogenital sinus B Uterine tube Uterine horns Rectum Anus Ovary Vagina opening Vagina & orifice Uterus Female Bladder ureter C Efferent ducts Epididymis Rectum Ductus deferens Undescended testis Anus Prostate gland Ureter Bladder Descended Testis in scrotum Penis Male

Congenital Malformations. RENAL Renal agenesislack of development. Dysplasiaabnormal development of nephrons and collecting ducts, form cysts Hypoplasiaagenesis of ureterhydronephrosis. Ectopic kidneys and ureters. Polycystic kidneysfailure of nephrons to join collecting ducts? REPRODUCTIVE SYSTEM Rectovaginal constriction at rectovaginal junctionhereditary Outpockecting of bladder when urachus fails to close. Cryptorchidismfailure of normal descent of testis. Mesonephric or paramesonephric duct abnormalitiesstenotic/aplasia of duct. Pseudohermaphroditegonads of one sex and external gentalia of the opposite sex, hormonal factors. True hermaphrodites is chromosomal abnormality during meiosis when the Y chromosome gets a fragment of the X chromosome, the gonad or ovo-testes gonad formed has both ovarian and testicular tissue. And hormones of both sexes are produced resulting in abnormal external genitalia. Freemartin cattle intersexuality, a genotypic female(XX) born with normal male co-twin due to fused placental vessels resulting in the transport of foetal androgens to the female.

Summary The urinary system and genital system are derived from the intermediate mesoderm,the nephrogenic plate and genital ridge of the urogenital ridge. Three kidneys develops in rapid successionpronephros, mesonephros and metanephros in cranial-caudal direction. Pronephros is of limited function in mammals is inducer mesonephros. The metanephros forms from two precursorsthe ureteric bud and the metanephrogenic mass.Development of the metanephros requires reciprocal tissue interaction using several molecular signals. Sex determination is dependent upon interaction of several factorsGenetic sex, gonadal sex, hormonal action and phenotypic sex. Germ cells are endodermal, the other tissues are mesodermal. Early in development, germ cells migrate from the yolk sac to the genital ridge. Development of the urogenital system is dependent on molecular signals. The external urinary and genital organs are formed from the cloaca and urogenital sinus. The Wolffian and Mullerian ducts form the adult male and female ducts respectively.

References 1. Gilbert, Scott.F(2003). Developmental Biology. 6th.Edition. pp447-461, 523-540, 548-561, Sinauer Associate. Massachusetts. 2. McGeady, T.A., Quinn, P.J., Fitzpatrick, E.S., & Rayan, M.T., (2006). Veterinary Embryology. Page 233-241; 244-265 3. Noden, M. and de Lahunta(1985). The Embryology of Domestic Animals, pp 312-341, 349-355 Williams and Wilkins, London.