4. Sex determination

Question 1

Define sex determination

Answer 1

Sex determination - process of development of sex differences - phenotypic development of structures upon hormone action produced after gonadal determination

Question 2

How many genes are in X/Y chromosome

Answer 2

X ~800-1000 genes
Y ~78 genes

Question 3

What determines the sex of the offspring?

Answer 3

Father - X/Y sperm

Question 4

What is bipotential indifferent stage?

Answer 4

A reproductive organ until week 7 of development which is sexually undetermined - has the potential to develop into two fates: ovary/testis

Question 5

What are the main reproductive cells?

Answer 5

Germ cells in gonads: oocyte / sperm

Somatic cells in gonads: granulosa, theca / Sertoli, Leydig

Question 6

Explain what are primordial germ cells

Answer 6

PGCs:
- precursor of egg / sperm
- large spherical sex cells
- specification of PGCs into eggs / sperm around week 3
- PGCs first located outside the embryo - in yolk sac - migrate into embryo gonadal / genital ridge

Question 7

Describe how PGCs migrate

Answer 7

Migration: PGCs migrate into genital ridge: through hindgut -> dorsal mesentry -> genital ridge

Proliferation: mitosis while migrating from ~100 -> 25000 cells -> divide into two populations - colonise left + right gonads

Question 8

What is the fetal kidney system?

Answer 8

Fetal interim kidney - mesonephros - later degenerates -> develop normal adult kidneys

Question 8

What does PGC motility require?

Answer 8

PGC motility requires:
- chemotaxis signals (TGFβ, Kit ligand/SCF, bFGF)
- gradients of ECM glycoproteins
- PGC-PGC contact

Sex specific PGC differentiation begins only after gonad colonisation - PGC -> prespermatogionia/prospermatogonia or oogonia

Question 9

What is the main gene regulating gonadal development beyond indifferent stage?

Answer 9

Steroidogenic factor 1 gene (SF1) - in SF1 KO mice gonads fail to develop beyond indifferent stage

Question 10

What are the main steps of sexual development?

Answer 10

Primary sex determination
Secondary sex differentiation

Question 11

What is the Jost paradigm?

Answer 11

Jost paradigm - default sex development - female

Alfred Jost - removed ovaries / testis from fetal rabbits - allowed to develop in utero - both developed into female - when injected testosterone - developed into males
=> sexual dimorphisms arise because fo testicular hormone production

Question 12

What are the hormones produced by testis that drive male development?

Answer 12

• Testosterone - secreted by Leydig cells
• Anti-Mullerian hormone (AMH) - secreted by Sertoli cells

Question 13

How does female reproductive system develop from indifferent bipotential stage?

Answer 13

Wolffian duct regresses because no testosterone or AMH

Question 14

How does male reproductive system develop from indifferent bipotential stage?

Answer 14

Mullerian duct has AMH receptors - when AMH released from Sertoli cells - signal for Mullerian duct regression

Question 15

PGC development overview

Answer 15

Question 16

What gene determines the sex of the organism?

Answer 16

SRY gene on Y chromosome - initiates testis development - encodes genetic TF - expressed in male somatic cells - Sertoli cells

Needed at a specific time window - only induces testis development if SRY expressed E10.5-12.5

Question 17

What happens if XY KO SRY gene?

Answer 17

XY KO SRY develops into female but with reduced fertility / infertile

Question 18

What happens if XX KI SRY gene?

Answer 18

XX KI SRY develops into male but no sperm - more male specific genes required from Y chromosome than just SRY

Question 19

If SRY gene codes for TF - what is the target?

Answer 19

SRY TF target - SOX9 gene - induces testis development

Question 20

What is needed for AMH expression in Sertoli cells?

Answer 20

SRY TF -> SF-1 TF -> AMH expression

Question 21

Male sex determination summary

Answer 21

Question 22

It is thought that female sex determination is default but what made question

Answer 22

Now not known any gene that would specifically produce ovaries - but XY twins born with X duplicated DAX1 gene -> develop into females

Question 23

Which gene is important for ovarian development?

Answer 23

Evidence for β-catenin signalling induced by Wnt4 - expression maintained in ovaries

XY with duplication of Wnt4 overexpress DAX1 and develop ovaries

Question 24

What are the three types of disorders of sex development (DSD)?

Answer 24

DSD types:
- sex chromosome: numerical / structural problems - Turner (XO), Klinfelter
- 46 XX: androgen excess in pregnancy - XX develops as male
- 46 XY: defect in steroidogenesis - abnormal testis development - ex: 5a reductase deficiency - if born female in puberty develops male characteristics

Question 25

What type of sex determination is in humans vs ants/flies vs turtles/alligators?

Answer 25

Humans - chromosomal sex determination - XX/XY

Flies - ratio of sex X chromosomes:autosomes

Ants - fertilized diploid eggs = females, unfertilized haploid eggs = males (males don’t have fathers, only mothers)

Turtles / alligators: environmental determinants: sex determined after fertilization by the env - temperature during specific developmental time window

Question 26

What is an example of environmental sex determination?

Answer 26

Question 27

What is an example of sex reversal?

Answer 27

Question 28

What is the cause why sea turtle populations have become increasingly female?

Answer 28

Thermosensitive sex determination - global warming - at higher temp females develop