19.04.17 Sex determination Flashcards
What is sex determination?
Determines whether gonads develop into testis or ovaries
- Either develop from bi-potential gonads
- Process is controlled by transcriptional regulators
What is sex differentiation?
Process of establishing phenotypic sex (internal and external genitalia)
- Process mainly controlled by secreted hormones (from the gonads) and their receptors
What are urogenital ridges?
Common precursors of the urinary and genital systems. Both male and female genital ducts are derived from mesonephros
Sex determination is a battle between what two systems?
1) male regulatory gene network in which the SRY gene activates SOX9
2) Female network involving RSPO1/WNT/β-catenin signalling
Describe the general scheme of sex determination
1) At gestation male and female embryos differ only by karyotype
2) At week 4, the urogenital ridge/bi-potential gonad has developed from the intermediate mesoderm
3) At week 6/7 - both female ans male foetuses have bi-potential gonads and two sets of internal ducts (Mullerian duct and Wolffian duct)
4) At this stage the external genitalia are identical
5) Lots of genes expressed in bi-potential gonads during development
- WT1, SF1/NR5A1, LHX9, LIM1, PAX2, GATA4, WNT4 etc
- WT1, SF1/NR5A1, GAT4A - also involved in male system
- WNT4 also involved in female system
6) Sex determination begins at week 7 where bi-potential gonad starts to develop into male or female
What specific genes are involved in the early development?
- Genital ridge is exposed to SF1, WT1 and LHX9
- Bi-potential gonad then forms.
- Bi-potential gonad then moves in one of two ways depending on exposure to these genes:
1) DAX1 and WNT4a - develops into female system
2) SRY and SOX9 - develops into male system
What happens in the female development?
- Occurs in absence of SRY - causes RSPO1 to be upregulated - that upregulates WNT4 - that activates β-catenin pathway
- WNT4 and beta-catenin both suppress SOX9 expression
- Ovary makes theca and granulosa cells
- Together these cells synthesise oestrogen
- Under the influence of oestrogen, the Mullerian duct differentiates into female genitalia (uterus, oviduct, cervix, upper vagina)
- Fetus then develops secondary sex characteristics of a female
What happens in the male development?
- All initiated by presence of SRY - which upregulates SOX9 which in turn stimulates FGF9 and PGD2
- FGF9 and PGD2 help to maintain SOX9 expression (through a positive feedback loop) - suppressing female development
- Testis have sertoli cells and leydig cells
- Sertoli cells - SF1 gene causes them to produce AMH which causes the regression of the Mullerian duct
- Leydig cells - SF1 gene causes them to produce testosterone
1) Testosterone - causes differentiation of the Wolffian duct into the male internal genitalia (epididymis, vas deferens, seminal vesicle)
2) In the urogenital region, testosterone is converted to dihydrotestoesternone (DHT), and this causes the development of the penis and prostate gland
Examples of mutations in female development genes
1) WNT4 - LoF variants cause masculinisation
2) RSPO1 - important role in downregulation of SOX9 - LoF associated with XX masculinisation
3) β-catenin - LoF associated with XX masculinisation -gain of function associated with XY female development
Examples of mutations in both male and female development genes
1) DAX1 - Involved in repression of male pathway in female development, but also required at low levels for normal male development. LoF associated with CAH. Overexpression may lead to XY sex reversal
2) 1) SF1 - Role in regulation of SOX9 gene. LoF associated with XY female development / XX primary ovarian insufficiency
Examples of mutations in male development genes
1) SRY - LoF results in XY female development, accounts for 15% of XY gonadal dysgenesis. SRY detected in 90% of apparent XX males
2) SOX9 - LoF associated with XY gonadal dysgenesis and campomelic dysplasia (severe skeletal malformations). GoF associated with XX male development
3) FGF9 - Involved in maintaining expression of SOX9. FGF9 null mice show XY female development
4) GATA4 - Critical to SRY activation. LoF associated with CHD and some cases of XY gonadal dysgenesis
When does sex differentiation begin?
Once development of gonads has begun, with the onset of hormone production
The angrodens affect the differentiation of the sexual organs including the brain
Steps of sex differentiation
- If testes develop and secrete testosterone, the Wolffian duct increases in size and differentiates into epididymis and vas deferens
- 5 α reductase 2 converts testosterone into 5a-dihydrotestosterone (DHT) which causes differentiation of the male urethra, prostate, penis, or scrotum
- Sertoli cells secrete anti-mullerian hormone (AMH) results in mullerian duct regression
- If testes do not develop, the wolffian duct does not grow and degenerates, and the mullerian duct proliferates and produces female organs
Is estrogen required in both male and female differentiation? and if so, what for?
Yes
- in females its needed for the mullerian duct to differentiate into its components
- in males its needed for fertility - it induces the vas deferens to absorb water and concentrate the sperm
- its also needed at puberty
List the hormones produced during male development
1) AMH by sertoli cells - causes regression of mullerian duct
2) Testosterone by leydig cells - acts via androgen receptor in the wolffian ducts to induce formation of epidyimis, seminal vesicles etc
3) INSL3 by leydig cells - causes tested to descend into scrotum
4) DHT formed from testosterone - causes masculinisation
