Normal Sexual Differentiation

Sexual Determination is a genetically controlled process dependent on the Y chromosome switch. Sexual differentiation is the process by which internal and external genitalia develop as male and female The processes have several stages and are contiguous

The SRY gene is the sex determining region (Y) creates the testis. It switches on during embryo development (>7weeks) to make the gonad into a testis SRY region is located between the pseudoautosomal region and euhromatin on the chromosome Testis develops 2 cell types: • Sertoli cells (makes AMH) • Leydig cells (makes testosterone) These hormones now enable phenotypic sexual development

• SRY is a DNA binding protein that acts as a transcription factor • The critical site for where the DNA binds is upstream of SOX 9 (another transcripton factor) • There is a positive feedback mechanism between binding to SOX 9 and SRY, however SOX 9 remains high even if SRY declines as it can bind its own activation site • SRY sends signals to turn off ovarian genes and turns on testicular genes. SRY turns on SOX 9 (Sox 9 also turns itself on) to KEEP off the ovarian genes and turn on testicular genes

• SOX 9 stimulates production of Prostaglanding D2 from pre- sertoli cells • D2 stimulates further SOX 9 production in pre- sertoli cells (second positive feedback) • SOX 9 stimulates FGF 9 (Fibroblast growth factor 9). This is a chemotactic factor for cell migration into the developing testis+ stimulating SOX 9 production- 3rd positive feedback • SOX 9 stimulates AMH which causes regression of mullerian ducts which develop into uterus and fallopian tubes in the female. Leads to inhibition of WNT 4 and FOX L2 • (look at slide for transcripiton pathway for XY and XX)

After fertilisation a pair of gonads develop which are bipotential. Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3½ - 4½ weeks) on posterior wall of lower thoracic lumbar region.

1) Primoridal germ cells become sperm or oocytes 2) Primitive sex cords become sertoli or granulosa cells 3) Become blood vessels and Leydig cells (male) or Theca cells (female)

An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks. They then migrate to the connective tissue of the hind gut, to the region of the developing kidney and on to the genital ridge – completed by 6 weeks.

Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords. • Expression in males: SRY expression Penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules. Eventually become Sertoli Cells which express AMH • No SRY (FEMALES) Sex cords ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – precursor of ovarian follicle Eventually become Granulosa cells.

These originate in the mesonephric primordium which are just lateral to the genital ridges. • In males they act under the influence of pre-sertoli cells (which themselves express SRY) to form… Vascular tissue Leydig cells (synthesize testosterone, do not express SRY) Basement membrane – contributing to formation of seminiferous tubules and rete-testis • In females without the influence of SRY they form… Vascular tissue +Theca cells.

• Mullerian ducts most important in female inhibited in the male by AMH • Wolffian ducts most important in the male stimulated by testosterone lack of stimulation by testosterone means regression in female

Testosterone is converted in the genital skin to the more potent androgen DHT (dihydrotestosterone) by 5-a-reductase. DHT binds to the testosterone receptor, but is more potent than testosterone.

the view that gender assignment of a newborn with ambiguous genitalia can be made regardless of the endocrine history.

the idea that a tendency for male or female is already present in neonates as a result of prenatal factors such as the hormonal milieu in utero.