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BIOL2045 > Sex determination > Flashcards

Sex determination Flashcards

1
Q

LO

A
  • To explain the fate of the genital ridges
  • Be able to describe the fate of germ cells in the ridges.
  • Be able to explain why fate of germ cells leads to lifelong fertility in men, but menopause in women.
  • Explain the importance of retinoic acid in sex determination.
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2
Q

Tell me about germ cell development in mice and when the determination between males and females can be seen?

A
  • Up to this point there is no observable difference between male and females… things now change!
  • The genital ridges are unique- all other organ primordia can form only one structure –they are bipotent the choice between the two is determined by the SRY gene in mammals
  • After 6 weeks the difference between males and female can be seen
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3
Q

The genital ridge forms at the same time as what other ridge?

A

Mesonephric ridge

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4
Q

What can the Wolffian act as?

A

An immature kidney at this early stage

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5
Q

How long is it for the Müllerian duct to form?

A

it forms after 6 weeks and above it is the wolffian duct

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6
Q

Can you start to identify between males and females after 6 weeks?

A

yes

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7
Q

The Y-chromosome gene is essential for male development

A
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8
Q

Tell me about the location of the SRY gene?

A

Right at the end of the p arm of the Y chromosome

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9
Q

The SRY gene is a member of what family?

A

A member of the Sox family of transcription factors

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10
Q

What does the SRY gene show?

A

Massive evolutionary changes

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11
Q

SRY gene

A
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12
Q

Tell me about conservation in the SRY gene?

A
  • Only High mobility group box- conserved at ~60 % mouse to man (about same level that HMG conserved between Sox family)
  • Outside the HMG there is 0 conservation
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13
Q

What cells is the SRY gene expressed in?

Tell me about the time line for this

A

SRY is expressed in the somatic cells of the male gential ridge

  • first at ~day 11 in mice – it is needed for only 6-12 hrs (in mice) as it turns on expression of Sox9 -another transcription factor
  • Sex determination is not a highly conserved mechanism in the animal kingdom
  • In situ hybridization
  • Note chords start forming at 13.5 d in male – still express Sox9
  • Difference between the two is due to the expression of SOX9
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14
Q

In mammals, what does the SRY drive?

A

Sox9 expression

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15
Q

Tell me about the sex genes in birds and the shared evolutionary male gene with mammals

A
  • In birds, the homogametic sex is male (ZZ) and the female (ZW) -high levels of DMRT1 present on the Z chromosome drive expression of Sox9

(a gene dosage)

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16
Q

Tell me about the reptiles expression of Sox9 and what its related to?

A
  • In some reptile’s expression of Sox9 is related to temperature
  • Alligator eggs incubated at
  • 33˚C 100% male (high temperature causes SOX9 to be released)
  • 30˚C 100% females
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17
Q

Is there SRY selection in monotremes?

A

no

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18
Q

Tell me about Sox9 expression between animals?

A

Mammals: SRY gene drive Sox9 expression

Birds: DMRT1 gene drive Sox9 expression

Reptiles: Sox9 expression relates to temperature

Snake/ Turtles/ Alligators: no X/Y/Z but temperature dependent expression of Sox9

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19
Q

What type of transcription factor is Sox9?

Tell me about its feedback loop

A

Sox9 is an autosomal transcription factor

its expressed in a positive feedback loop with its own gene (this is relatively rare)

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20
Q

What does Sox9 block?

A

It blocks ovary formation by the genital ridge (stops function of the paracrine Wnt/β-catenin pathway)

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21
Q

What does Sox9 activate the expression of?

A
  • Activates expression of Anti-Mullerian Hormone (by the male genital ridge)- more a paracrine then a hormone but it’s given the name of hormone
  • Activates expression of FGF9 (in another positive feedback loop with Sox9- makes more of its self and SOX9) in the (male) genital ridge
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22
Q

What type of messenger system is beta-catenin?

A

A secondary messenger system

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23
Q

What is FGF9?

A

Paracrine signalling molecule formed by the somatic cells of the genital ridge

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24
Q

What does FGF9 cause?

A

Causes proliferation of some genital ridge cells to form Sertoli cells and formation of chords of cells – gives the typical tubular structure of the testis later (seminiferous tubules)

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25
Q

What does FGF9 repress?

A

Represses (with Sox9) the Wnt/β-catenin path so blocks ovary formation

26
Q

What does FGF9 coordinate?

A

Coordinates differentiation pathway of PGCs

27
Q

What do sertoli cells act as?

A

nurse cells for male PGCs

28
Q

The path of the male genital ridge

(piecing together everything discussed before this)

A
29
Q

Where is testosterone produced?

A

produced by the intestinal cells of the testes

30
Q

What does testosterone allow?

A

The growth of the Wolffian (mesonephric) duct to form the epididymis and the vas deferens

31
Q

What does testosterone drive?

A

The secondary sex determinants

32
Q

Tell me about what the loss of the androgen receptor produces?

A
  • Loss of the androgen receptor produces female appearance but with retained testes
  • Intersex- failure in genetic and anatomic correlation
33
Q

Tell me about secondary sex determinants

A

secondary sex determinants – in early development formation of penis etc so if no testosterone female external phenotype

34
Q

Testostermone more information…

A

Often (not always) immature testes but always failure of Wolffian duct so no (or vestigal)- vas deferens/epididymis

35
Q

What signal remains high in the female genital ridge?

A

Wnt 4 (paracrine signal) expression remains high in the female genital ridge (reduced/lost in males)

36
Q

Tell me about the signals that lead to the production of the epithelium of the ovary to form granulosa cells surrounding the PGCs/ follicles

A
  • Signals through the second messenger β catenin (over-expression in males causes an ovary to form eg TG mice)
  • Induces expression of a series of ovary specific transcription factors and paracrine signals – including the secreted signal Follistatin- which induces the epithelium of the ovary to form granulosa cells surrounding the PGCs/follicles
37
Q

In the female the müllerian duct is not lost, instead what does it differentiate into?

A

uterus, oviducts and cervix

This is the default pathway in the absence of SRY/Sox9/FGF9

38
Q

What does Follistatin cause?

A

Follistatin causes granulosa cells to form surrounding the PGCs rather than chords of Sertoli cells as in male

39
Q

Follistatin expression

A
40
Q

In the absence of testosterone, what is lost (in females)?

What grows instead?

A

The Wolffian duct

The Mullerian duct grows (no AMH- anti-Mullerian hormone as this is a male specific thing) to develop the ovarian ducts, uterus cervix and top of vagina

Wolffian duct = mesonephric duct

41
Q

Gender differences- PGCs

A
42
Q

Gender differences- how male and females differ in their reproductive lifespan

A
43
Q

Tell me about the female gamete lifespan

A

Women: Born with a FINITE number of eggs. With age these eggs are used up (they mostly die, but some get ovulated). By age 51 years (on average) women reach MENOPAUSE.

44
Q

Tell me the following species which show menopause?

A
  • killer whales
  • short-finned pilot whales
  • belugas
  • narwhals
45
Q

Tell me about the lifespan of male gametes

A

Men: Born with a capacity to continuously produce mature sperm from PUBERTY throughout life.

46
Q

Why is it thought that the male gamete lifespan is longer than womens?

A
  • Eggs are costly to make, women make enough to last their entire life (true for most of our evolutionary past).
  • Older women undergo menopause so as to be able to nurture existing children, and not leave very young children motherless.
  • Eggs most die before birth – 1-2 million at birth – a few 100s ovulated (300-400)
  • 2000 yrs. ago few women lived to 51
  • Human Female reproductive cycle is costly even if no pregnancy occurs
  • NB no menopause in other primates
47
Q

Fate of PGCs is gender dependent

A
48
Q

Diagram to illustrate gender dependent PGC fate

A
49
Q

Why do females enter meiosis?

A
  • Retinoic Acid (RA) induces meiosis in females. (RA - the active metabolite of vitamin A)
  • There are very high levels of RA about the genital ridge
  • RA diffuses into the PGCs and causes the expression of Stra8 (Stimulated by retinoic acid)
50
Q

Tell me about the Stra8

A
  • Stra8 is a transcriptional regulator, modifying the gene expression pattern in the cell.
  • Stra8 is ‘the master switch’ for meiosis. It causes PGCs in female embryos to stop dividing mitotically and enter meiosis.
  • Difference – male and female fate of PGCs
  • Stra- Stimulated by Retinoic Acid- here 9th gene discovered
  • All Stra genes have an RRE sequence in their promoter – retinoic response element – RA enters the cell (lipophilic) and binds to promoter
51
Q

Where is retinoic acid made?

A

RA is made not in the genital ridge (G), but in the Mesonephros (M).

52
Q

Where is the Mesonephros located?

A

The Mesonephros is next to the genital ridge (it goes on to form parts of the epididymis and vas deferens in males, but regresses, in females).

53
Q

Mesonephric tubules (T) and ducts (D) (D-wolffian duct) connects to what?

What does this mean about the diffusion of RA?

A

The anterior end of the gonad

Therefore, RA diffuses into the genital ridge from the Mesonephros.

54
Q

Experimentally created XX/XY chimeras, all germ cells, both XX and XY, enter meiosis when present in what?

A

fetal ovary

55
Q

What stops PGCs in male foetal testis entering meiosis?

A

Stra8 levels do not rise in male PGCs

56
Q

How do the Stra8 levels not rise in male PGCs?

A

How: Fibroblast growth factor 9 (FGF9) produced by other male gonad cells

  • induces Cyp26b1 which degrades RA before it reaches the PGCs
  • represses Stra8 expression so inhibits meiosis entry

in the absence of RA –FGF9 maintains expression of pluripotency genes like NANOG/SOX2

  • Cyp-cytochrome enzyme
  • Pluripotency genes allows PGCs proliferation in the male later
57
Q

Cyp26b1 is an enzyme involved in the degradation of retinoic acid

A
58
Q

CYP26b1 is only present in male gonads

A
59
Q

Experiment showing only male produce Cyp26b1

A
  • Result of Cyp26b1 in the male is RA signal is blocked and no Stra8 – while in the female RA signaling occurs and Stra8 expression is seen
  • Loss of Cyp26B1 enzyme in males results in male PGCs entering meiosis in utero this results in an infertile male (has testis but no sperm)
  • Notice slight Cyp26b1 present before 11.5 – lost in female but maintained in male by expression of sry-sox9-fgf9 path which starts at E11.5
60
Q
A
61
Q

Summary

A
  • Predetermined (C. elegans) and inductive (mammals) germ cell development.
  • Inductive germ cells reach genital ridge following migratory journey. Only in females do germ cells enter meiosis when they reach the genital ridge.
  • SRY-SOX9-FGF9 pathway converts the default female genital ridge to a male outcome
  • RA causes meiotic entry of PGCs in females by activating Stra8, but Cyp26b1 (under control of SRY/ SOX9/FGF9) degrades RA in males.

BIOL2045 (14 decks)

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