SEXUAL DEVELOPMENT

1. Richard E. Falvo, Ph.D.Adjunct ProfessorCell and Molecular Physiology School of MedicineUniversity of North Carolina -Chapel Hill Sponsoredby the Endocrine Society SEXUAL DEVELOPMENT

2. THE CHICKEN IS THE ******EGG’S****** WAY OF MAKING ANOTHER EGG

3. First Important Points about Sexual Differentiation/Determination • In the early human embryo, cells that are to become spermatozoa or ova, migrate to the gonadal area of the fetus which is not yet matured into either a testis or an ovary [ i.e, it is indifferent] • In the early human embryo, both male and female internal reproductive structures exist in all embryos, whether XX or XY • In the early human embryo, the external genitalia are “indifferent” - meaning that you cannot distinguish male from female. • In the early human embryo the hormonal environment changes the indifferent structures into either male or female.

4. Sexual Differentiation • Defined as the phenotypic development of structures after the action of gonadal hormones produced following gonadal development.

5. Sexual Determination • Defined as the commitment of the indifferent gonad to become either a testis or an ovary, a development that is genetically programmed in a critically timed and gene dosage-dependent manner.

6. In either an XX or XY fetus, in the absence of testes or ovaries The resulting human embryo will have female internal genital ducts and female external genitalia

7. Time in weeks of these key times. Indifferent gonad Two internal duct systems Indifferent external genitalia 4 5 6 7 8 9 10 11 12 13 14 15 40 Gestation Weeks

8. They can become either male [testes] or female [ovaries]. This occurs about 6-7 weeks in utero Once this decision is made - other cells within the gonads become either male or female as well. Coelemic epithelial cells can become either Sertoli cells or granulosa cells Mesenchymal cells can become either Leydig cells or thecal cells Primordial germ cells migrate from the yolksac endoderm to theplace where the gonads will form Primordial germ cells can become either oogonia or spermatogonia depending on where they become trapped [in either a testis or ovary The gonads are indifferent

9. Until the 8th week, the internal duct systems ofthe male and female are both present in all embryosWhen stimulated to develop - the Wolffian ducts become the epididymis, vas deferens and seminal vesicles When developed - the Mullerian ducts becomethe Fallopian tubes, uterus and upper 2/3 of vagina

10. Urogenital sinus and genital tubercle clitoris penis labia prostate lower vagina scrotum Until 9 wk, the urogenital sinus and genital tubercles are indifferent. Ultimately [14-15 wk] they differentiate into the external genitalia Provided by V Shea[UNC]

11. Gonad Wolffian duct [male] Mullerian duct [female] At 8/9 wks gestation Urogential sinus + genital tubercle

12. Let’s summarize Indifferent gonad - germ cells migrate here Two internal duct systems Indifferent gonad becomes either testes or ovaries Wolffian duct develops in male Mullerian duct develops in female External genitalia become male or female Indifferent external genitalia 4 5 6 7 8 9 10 11 12 13 14 15 40 Gestation Weeks

13. How does this all happen? Hormones Genes

14. Genes involved in sexual development Other genes are important as well. 1/2 of genes involved in early spermatogenesis are on the X Genes on the X have critical influence on sex determination in both males and females You can observe an 46XX male and a 46XY female due to sharing of the SRY gene between the Y and X chromosome. SRY - sex determining region on the Y chromosome. This will ensure testes will be formed!

15. Genes involved in female sexual development Absence of SRY is essential [i.e., not testis] Need 2X chromosomes for normal ovaries Inactivation of one X chromosome in each female cells occurs in human embryos during the blastocyst stage [12 - 18th day] - results in gene silencing in all progeny of that cell. Only germ cells are except from this gene silencing.

16. SRY gene expression No introns 900 bp transcript Protein - 204 residues Expressed until about 18wk gestation in Sertoli cells and also in adult Stertoli cells and germ cells.

17. Other genes involved in sexual development SOX 9 SF1 WT1 DMRT1 DAX1 WNT4 ATRX FOXL2 DHH We know these genes because of abnormalities that Result from deletions, mutations, missense mutations, translocations and duplications.

18. Hormones of Importance in Sexual Differentiation • Testosterone [T] - Leydig cells • Dihydrotestosterone [DHT] - tissue conversion from T • Anti Mullerian Hormone [AMH] -Sertoli cell glycoprotein • Estrogen

19. Male Sexual Development Testosterone Testis descent Sertoli cell activity Leydig cell activity Male external Genitalia diff. External genital growth Germ cell migration Wolffian duct differentiation 4 5 6 7 8 9 10 11 12 13 14 15 40 Gestation Weeks

20. Gonad Wolffian duct [male] Mullerian duct [female] Urogential sinus + genital tubercle

21. Testes Wolffian duct [male] Epididymis, Vas deferens, Seminal vesicles, etc. Penis, scrotum, prostate Urogential sinus + genital tubercle

22. Female Sexual Development Germ cell migration Mullerian Ducts remain 4 5 6 7 8 9 10 11 12 13 14 15 40 Gestation Weeks

23. Due to lack of testicular testosterone, Wolffian ducts don’t develop Due to lack of testicular Sertoli cells, no mullerian inhibiting hormone hence Mullerian ducts develop Estrogen Female external Genital growth Female external Genitalia differentiation Germ cell migration Mullerian duct development 4 5 6 7 8 9 10 11 12 13 14 15 40 Gestation Weeks

24. Gonad Wolffian duct [male] Mullerian duct [female] Urogential sinus + genital tubercle

25. Ovaries Mullerian duct [female] Uterus, fallopian tubes Clitoris, labia, vagina Urogential sinus + genital tubercle

26. XY Genotype Germ cells Presence of SRY gene on Y chromosome Primordial gonads Fetal testes Sertoli cells Leydig cells Dihydrotestosterone Anti - Mullerian hormone Testosterone Wolffian Duct Develop External genitalia -epididymis Mullerian Duct Regresssion -penis -vas deferens -prostate -seminal vesicles -scrotum

27. XXGenotype Germ cells No SRY gene Primordial gonads Fetal ovary Absence of anti -Mullerian hormone Absence of testosterone Mullerian ducts External genitalia Wolffian duct regression -uterus -vagina -Fallopian tubes -external genitalia

28. First Important Points about Sexual Differentiation • In the early human embryo, cells that are to become spermatozoa or ova, migrate to the gonadal area of the fetus which is not yet matured into either a testis or an ovary [ i.e, it is indifferent] • In the early human embryo, both male and female internal reproductive structures exist in all embryos, whether XX or XY • In the early human embryo, the external genitalia are “indifferent” - meaning that you cannot distinguish male from female. • In the early human embryo the hormonal environment changes the indifferent structures into either male or female.