Semmelweis University

1. Development of the gonads Dr. Nandor Nagy Semmelweis University

2. Levels of sex determination: Genetic sex: XX or XY sex chromosomes Gonadal sex: ovaries or testes Genital sex (phenotype): genital ducts external genitalia Gender identity

3. primordial germ cells (PGCs). PGCs can be first identified within the wall of the yolk sac, one of the extraembryonic membranes, during the 4th to 6th weeks of gestation. These PGCs will give rise to the germ line, a series of cells that form the sex cells, or gametes (i.e., the egg and sperm).

5. CXCR4 on the surface of PGCs SDF1 intestinal mesenhcyme and gonads Chemotropic signals (i.e., attractive signals produced by the developing gonads) also seem to be involved to regulate PGC homing. One such factor is the chemokine (a type of cytokine) Stromal cell-derived factor-1 (Sdf1) and its receptor Cxcr4. PGC migration toward the gonad is disrupted in mouse or zebrafish embryos lacking the ligand or its receptor. In addition, Sdf1 acts as a PGC survival factor.

6. Teratomas, tumors composed of tissues derived from all three germ layers, can be extragonadal or gonadal and are derived from PGCs.

7. From the wall of the yolk sac, PGCs actively migrate between the 6th to 12th weeks of gestation to the dorsal body wall of the embryo, where they populate the developing gonads and differentiate into the gamete precursor cells called spermatogonia in the male and oogonia in the female. Like the normal somatic cells of the body, the spermatogonia and oogonia are diploid; that is, they each contain 23 pairs of chromosomes (for a total of 46 chromosomes each).

8. SEXUAL DIMORPHISM Gonads: ovary testis Genital ducts: uterine tube epididymis uterus ductus deferens vagina Accessory sex glands: seminal vesicle paraurethral glands prostate greater vestibular gland bulbourethral gland External genitalia: clitoris penis labia majora scrotum labia minora Levels of sex determination: Genetic sex: XX or XY sex chromosomes Gonadal sex: ovaries or testes Genital sex (phenotype): genital ducts external genitalia Gender identity

9. In Absence of Y Chromosome, Female Development Occurs 44 XX: 44 YX Genetic sex: XX or XY sex chromosomes

10. KLINEFELTER Syndrome XXY---extra X chromosome /is one of the most common chromosome abnormalities in humans.  About one of every 500 males has an extra X chromosome, but many don’t have any symptoms. -small testis, reduced fertility -taller, less hair, larger breasts, broader hips, etc

11. Turner-Syndrome • X0 • It occurs in about 1 out of every 2500 female births • Underdeveloped ovaries • Infertility • Short stature, webbed neck

12. Gonadal development does not require the presence of germ cells

15. Indifferent gonads Ovary or testis: depend on the chromosomes

16. SRY gene(Testis Determinig Factor) X Y

17. The sexual differentiation of genetic males begins at the end of the 6th week, when a specific gene on the Y chromosome (SRY) is expressed in the somatic support cells. Embryos in which this gene is not expressed develop as females. The product of this gene, called the SRY protein, initiates a developmental cascade that leads to the formation of the testes, the male genital ducts and associated glands, the male external genitalia, and the entire constellation of male secondary sex characteristics.

18. 223 AA protein Az SRY is expressed only In the testis In the female embryo, the XX somatic support cells do not contain a Y chromosome or the SRY gene. Therefore, they differentiate as follicle cells instead of Sertoli cells.

20. Bipotential gonads before sexual development Adapted from Kobayashi and Behringer, Nature Reviews, 2003

21. Oviduct, uterus, and cervix develop from the Mullerian duct Adapted from Kobayashi and Behringer, Nature Reviews, 2003

22. Mullerian Inhibiting Substance (MIS)/AMH regresses formation of the Mullerian ducts in males Adapted from Behringer, Mouse Molecular Genetic Studies of Organogenesis Talk

23. MIS is necessary and sufficient for regression of the Mullerian duct Dr. Patricia Donahoe

24. MALE (XY): Sry gene on the Y chromosome leads to testes development Testes secrete testosterone and anti-mullerian hormone (AMH). AMH inhibits the development of the Mullerian ducts. Testosterone develops the wollfian ducts, penis, and scrotum, and masculinizes the brain. Dihydrotestosterone (DHT), a metabolite of testosterone, amplifies the local effects of testosterone on the external genitalia. FEMALE (XX): Lack of Sry gene leads undifferentiated gonads to develop into ovaries. Lack of AMH from the testes leads to unchecked Mullerian duct growth and no wollfian duct development. Lack of testosterone leads external genitalia to develop into the labia, clitoris, and outer vagina. Normal Sex Differentiation: A Review

25. Persistent müllerian duct syndrome. In 46, XY individuals with mutations in AMH or AMH RECEPTOR genes, the müllerian ducts fail to regress. These individuals develop müllerian derivatives, in addition to those from the mesonephric duct. These individuals have a cervix, uterus, and Fallopian tubes, as well as vasa deferentia and male external genitalia. The phenotype varies in that the female organs are in their normal position, but the testes may lie either in the normal position for ovaries (i.e., within the broad ligament, A), one testis may lie within the inguinal hernial sac (B), or both testes may lie within same inguinal sac (C). D, Phenotype typical of the scenario shown in A. The lower two arrows point to the Fallopian tubes, and the upper two arrows indicate the position of the testes within the broad ligament.

26. (androgen insensitivity syndrome) -testosterone binding protein mutation -woman with complete androgen insensitivity syndrome (CAIS) has a female external appearance despite a 46XY karyotype and undescended testes, a condition termed testicular feminization in the past.

27. GENITAL DUCTS male The SRY protein exerts autonomous control of somatic support cell development into pre-Sertoli cells. Pre-Sertoli cells then recruit mesonephric mesenchymal cells into the gonadal ridge and these cells give rise to Leydig cells, myoepithelial cells, interstitial cells, and endothelial cells. Differentiating Sertoli cells then envelop the germ cells and together with the myoepithelial cells organize into testis cords (future seminiferous tubules). Mesonephric duct derivatives: appendix epididymis ductus epididymis ductus deferens ejaculatory duct seminal vesicle Mesonephric tubule derivatives: efferent ductules: from epigenital tubules paradidymis: from paragenital tubules Paramesonephric duct remnants: appendix testis prostatic utricle – remnant of vaginal plate

28. Dax1 (Dosage sensitive sex reversal, adrenal hypoplasia congenita-critical region of the X chromosome, gene 1) is described as being an ovarian-promoting factor because it can act as an "anti-testis" factor. The human DAX1 gene is found on the X chromosome. No AMH, SRY!!!!

29. GENITAL DUCTS female Paramesonephric duct derivatives: uterine tube uterus upper part of vagina Mesonephric duct remnants: appendix of ovary epoophoron Gartner’s duct/cyst Mesonephric tubule remnants: epoophoron paroophoron

30. The ovarian follicles in ovotestis often mature to corpus luteum in adulthood. Some hermaphrodite patients raised as females have even become mothers.  In ovotestis, the seminiferous tubules remain small and rarely may show incomplete spermatogenesis.

31. HoxD12 HoxD genes Regulate the external genitalia development

32. EXTERNAL GENITALIA: indifferent stage The appearance of the external genitalia is similar in male and female embryos through the 12th week, and embryos of this age are difficult to sex on the basis of their external appearance Components: genital tubercle → phallus genital folds genital swellings Female Differentiation: phallus – clitoris genital folds – labia minora genital swellings– labia majora no fusion! Male Differentiation: phallus – penis (dorsal) genital folds – penis (ventral) genital swellings – scrotum fusion of genital folds and swellings!

33. 9.week 12.week