Normal Sex Differentiation

Question 1

Define Sexual Determination

Answer 1

Genetically controlled process dependent on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female.

Question 2

Define Sexual Differentiation

Answer 2

The process by which internal and external genitalia develop as male or female.

Question 3

What determines gonadal sex?

Answer 3

The y chromosome is the smallest chromosome, it doesn’t contain all the genes to make a male. BUT it does contain the SRY gene, located on the short arm of the y chromosome.

Question 4

The SRY gene is a transcription factor

Answer 4

This binds to DNA on other chromosomes – causing a cascade of genes leading to the formation of the testis.

Question 5

SRY gene creates testis (in the absence of Y chromosome ovaries develop)

Answer 5

Sex determining region Y (SRY) switches on briefly during embryo development (>week 7) to make the gonad into a testis. In its absence an ovary is formed

Question 6

Testis develops cells that make 2 important hormones

Answer 6

Sertoli Cell–> AMH
Leydig Cells–> Testosterone

Question 7

SRY and Sox 9

Answer 7

SRY is a DNA binding protein that acts as a transcription factor.
It turns off many ovarian genes and turns on testicular genes

SRY also binds DNA upstream of itself, causing transcription of itself. Positive feedback

The critical site of DNA binding is upstream of SOX9 which is also a transcription factor.
SOX9 can bind its own upstream activation site so its levels remain high even if SRY declines. This is a positive feedback mechanism.
SOX9 then acts to stimulate the expression of further downstream genes

SRY determines executive policy and SOX9 implements it.

Question 8

What is the mechanism of SRY action?

Answer 8

Main role is switching on SOX9

Question 9

How does SOX9 achieve its effects?

Answer 9

Stimulates production of prostaglandin D2 (PGD2) by the pre-sertoli cells. PGD2 acts as a paracrine hormone to stimulate further SOX9 production in these cells. This second positive feedback mechanism serves to re-enforce all precursor cells along the sertoli pathway.

SOX9 stimulates production of fibroblast growth factor 9 (FGF9). FGF9 acts as a chemotactic factor for cell migration into the developing testis. It also further stimulates the production of SOX9 a third positive feedback mechanism.

SOX9 stimulates the production of anti-Mullerian hormone (AMH). AMH causes the regression of the mullerian ducts which develop into the uterus and fallopian tubes in the female.

Inhibition of female transcription factors WNT4 and FOXL2

Question 10

Transcriptional pathways

Answer 10

Y chromosome -> SRY -> SOX9 -> AMH -> Leydig cells and sperm
XX - > Wnt4 and FOXL2 -> Theca cells and oocytes

Question 11

Gonadal development

Answer 11

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.

Purple = Genital ridges that will become a pair of testes or ovaries

Mullerian duct = Female – becomes uterus (internal genitalia)
Wolffian duct = Male – becomes vas deferens, seminal vesicles

Question 12

Genital ridge- 3 waves of cells invade the genital ridge, they are?

Answer 12

Primordial Germ Cells – become Sperm (male) or Oocytes (female).

Primitive Sex Cords – become Sertoli cells (male) or Granulosa cells (female). Depends on Y

Mesonephric Cells – become blood vessels and Leydig cells (male) or Theca cells (female). Will produce androgens

Question 13

Describe primordial germ cell mutation

Answer 13

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.

They wait to receive signals from a Sertoli cell or a granulosa cell – this decides if they become sperm or become oocytes.

Question 14

Primitive sex chords

Answer 14

Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords.

The primitive sex chords are a layer on top of the surface of the genital ridge
They migrate inwards and will either become Sertoli cells or granulosa cells

Question 15

Male vs Female primitive sex chords

Answer 15

Male:
- SRY expression
- Penetrate medullary mesenchyme & surround
primordial germ cells to form testis cords –
precursor of seminiferous tubules.
- Eventually become Sertoli Cells which express AMH

Female:
- No SRY
- 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 16

Mesonephric Cells

Answer 16

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 17

Gonadal Sex Summary Males

Answer 17

Primordial germ cells–> Spermatozoa
Primitive sex cords –> Sertoli cells (SRY, AMH)
Mesonephric cells –> Leydig cells (Androgens)

Question 18

Gonadal Sex Summary Females

Answer 18

Primordial germ cells –> Oocytes
Primitive sex cords –> Granulosa cells
Mesonephric cells –> Theca cells

Question 19

Internal Reproductive Organs

Answer 19

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 20

5-alpha-reductase and External Differentiation

Answer 20

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

DHT causes differentiation of the male external genitalia:
* Clitoral area enlarges into penis
* Labia fuse and become ruggated to form scrotum
* Prostate forms

Question 21

Sex and Gender

Answer 21

Sex
The biological aspects of an individual as determined by
their anatomy, which is produced by their chromosomes
& hormones etc

Gender
Defined as a social construction relating to behaviours
and attributes based on labels of masculinity and
femininity.

Question 22

Gender Identity

Answer 22

The personal, internal perception of oneself. An individual may see themselves as a man, woman, as having no gender, or as having a non-binary gender, where people identify as somewhere on a spectrum between man and woman.

Question 23

Gender Role

Answer 23

Expression or portrayal of psychological characteristics that are considered sexually dimorphic within the general
population (eg. toy preferences / physical aggression etc).

Question 24

Sexual Orientation

Answer 24

Preference of sexual partner and erotic interest (eg. include heterosexual, bisexual, homosexual).

Question 25

Psychosexual neutrality

Answer 25

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

Question 26

Neural bias

Answer 26

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

Question 27

Hormones & behaviour

Answer 27

Exposing animals to sex hormones during a critical period before or just after birth is associated with
sexually divergent behaviour.

Dog breeders wait until the dog has learned to cock its leg before neutering. If they are neutered
early, this behavior never develops.

Treatment of female mice with testosterone in first 5 days of life increases their display of masculine sexual behaviour in adulthood and decreases female patterns.

Castration of male rats during this period removes the influence of androgens and has the reverse effect.

Androgens may influence the development of these behavioural differences by acting on the structure of the developing brain.

Question 28

Gender difference in the brain

Answer 28

Numerous genes are differentially expressed in male and female embryonic brains.

Both morphological and functional differences in human brain structure according to sex have
been described.

Neuroimaging has shown functional sex differences in a variety of brain regions when subjects
have undergone activities related to:
emotion, memory, learning, language, olfaction, vision, hearing, navigating, processing of faces
and pain perception

Evidence has indicated certain tasks showing bilateral differences between genders.

Question 29

Functional magnetic resonance images (fMRI) males and females reading out loud (phonological processing).

Answer 29

fMRI Detects changes in blood oxygenation and flow that occur in response to neural
activity – when a brain area is more active it consumes more oxygen and to meet this
increased demand blood flow increases to the active area.

Female brain- more active than male brain

Question 30

Gender difference in the brain

Answer 30

Amygdala larger in males? A brain region involved in
emotional processing. Its size is positively correlated with
aggressive behaviour across species.
Left amygdala more active in women? Associated with
emotional memories.
Hippocampus contains more grey matter in females?
Involved in memory & social cognition.
The third interstitial nucleus of the anterior hypothalamus
(INAH-3) has been suggested as a major determinant of
sexual identity. It may be larger in heterosexual males than
in homosexual males and heterosexual females.

Question 31

Social learning- Does gender assignment at birth tend to reinforce some developing behaviours and not others?

Answer 31

When adults are handed a baby and told whether it is a
boy or girl their play and communication with it differ
according to their perception of its sex.
In one study adults watched a film of a child at play, half
were told it was a girl and the other half told it was a
boy. When the child was startled, those who thought it
was a boy more often regarded it as angry, whereas
those who believed it was a girl tended to interpret the
startled look as a sign of distress.

Question 32

Social Learning- gender stereotypes and labelling

Answer 32

By the age of 2 children consistently label themselves as male or female.
By the age of 5 they appear to have a sense of gender constancy ie. they believe that gender cannot
be changed.
When 3 – 6 year olds are shown a video of children at play their descriptions are different according
to whether they are told it’s a boy or girl. They appear to be more rigidly gender stereotyping than
adults performing the same task.
The evidence supports the view that
gender stereotypes are applied to babies;
and children themselves use and apply
them from an early age.

Question 33

Summary

Answer 33

Some gendered patterns of behaviour may be induced by the way boys and girls are
treated or as a result of the expectations of others.
Differentiation of the human brain is partly due the hormonal environment in utero
and/or neonatally.
Even before foetal hormone levels rise there are numerous genes expressed
differently in male and female brains.
Psychosexual development is not fully understood and remains the focus of active
research and investigation.