Normal Sexual Differentiation

Question 1

Sexual determination vs differentiation

Answer 1

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

Question 2

Gonadal Sex Determination

Answer 2

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

Question 3

Explain mechanism of SRY action

Answer 3

• 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

Question 4

How does SOX 9 achieve its effects?

Answer 4

• 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)

Question 5

Describe Goandal Development

Answer 5

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.

Question 6

Genital ridge- 3 waves of cells

Answer 6

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)

Question 7

Primordial germ cell migration

Answer 7

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.

Question 8

Primitive sex cords (sertoli/granulosa)

Answer 8

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.

Question 9

Mesonephric cells

Answer 9

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.

Question 10

2 internal reproductive organ types: Wolfiann and Mullerian ducts

Answer 10

• 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

Question 11

5 alpha reductase and external differentiation

Answer 11

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.

Question 12

Psychosexual neutrality

Answer 12

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

Question 13

Neural bias

Answer 13

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.