lecture 23: diseases and disorders 1: non-human sex differentation Flashcards Preview

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Flashcards in lecture 23: diseases and disorders 1: non-human sex differentation Deck (24):
1

What is vertebrate phylogeny?

  • hormonal influence 
    • gold fish
    • frog
    • snakes
    • birds
  • genetic influence 
    • platypus → XY chromosome arise 
    • kangaroo
    • mouse
    • human
  • common ancestory drosophila 

2

What are different animal models of sexual differentiation?

  • mouse model (Genetic sex determination, XY/XX)
  • marsupial model (GSD, XY/XX)
  • avian model (GSD, ZW/ZZ)
  • reptile model (environmental sex determination)
  • fish sex differentiation (GSD/ESD)
  • drosophila (GSD, XY/XX)
  • nematode sex differentiation (XO/XX)

3

What are sexual differentiation events?

  • days from fertilisation
  • E9.5 germ cell migration to gonads 
  • E10.5 indifferent gonads, onset of testicular differentiation 
  • E10.5 to 12.5 sex determination window 
  • E13.5 onset of ovarian differentiation 
  • E13.5 entry into meiosis 

4

How do testes develop in the mouse?

  • testis cord in testes
  • adjacent to mesonephros 
  • germ cells are surrounded by sertoli cells, PM cells to form testis cords  
  • leydig cells reside outside testis cords 

5

What is gonad development in the mouse embryo?

  • Sf1, Wt1, Lhx9, M33, Emx2 → at this stage gonad has potential to form testis or ovaries  
  • E10.0-11.5 - indifferent gonad 
    • SRY → SOX9 (Fgf9 [important for proliferation of somatic cells and differentiation of sertoli cells], AMH [important for regression of the mullerian duct], Dmrt1 [related to double sex in drosophila, promotes and maintains testis development]) → E12.5 XY gonad 
    • wnt 4 Fst → E12.5 XX gonad → E18.5 XX gonad 

6

What is the model of sex development in the tammar wallaby (marsupial)?

  • postnatal development → short gestation, long lactation 
  • before birth there is no difference between testis and ovary
  • male: 
    • onset of testicular differentiation v soon after birth (before 1 day) 
    • testicular cords visible from day 2 
  • female 
    • onset of ovarian differentiation 6.5 days after birth 
    • cortex and medulla visible ~8 days
    • slower 

7

What determines sex differentiation in the marsupial?

  • GSD XX:XY (SRY) 
  • marsupial key sex determining and differentiation genes 
    • SRY, Sf1, Fgf9 → Sox 9 → male specific targets 
    • master regulator → Wnt4 (beta catenin → female specific targets), FoxI2 (aromatase → E2-ER, inhibits Sox9, female specific targets, self promotion)

8

What is eostrogen sex reversal?

  • testes become ovary when treated with oestrogen 
  • formation of cortex and medulla 

9

What was seen when doing RT-PCR of the cells in the E2-treated testes?

  • SRY and AMH are greatly downregulated when treated with E2
  • however SOX9 levels had no change
  • where is SOX9 located

10

What is the sox9 protein distribution in sex reversed testes?

  • cytoplasmic 
  • usually in sertoli cell nucleus 

11

What is the effect of oestrogen treatment on the female pathway?

  • genes are greatly upregulated 

12

So what is the effect of oestrogen on the sex differentiation pathway?

  • inhibits SRY 
  • inhibits nulcear sox9
  • inhibits AMH
  • therefore inhibits testis
  • upregulates female pathway leading to development of ovary e.g. Wnt4, FoxL2 

13

What is sex determination in the chicken?

  • genetic sex determination
  • ZZ (male): ZW (female) 
  • testis
    • seminiferous cords
    • reduced cortex
    • arrested germ cells
  • ovary 
    • fragmented medulla 
    • thickened cortex 
    • meiotic germ cells 

14

What is gona development in the chicken?

  • at 4.5 days the gonads are undifferentiated 
  • morphological differentiation incubation day 6.5
  • lots of genes are expressed in these processes 
  • SF1 
  • two genes important for the male pathway: Dmrt1, SOX9
  • different chromosomes, conserved genes 

15

How is sex determined in most reptiles?

  • environmental 
  • temperature sex determination in reptiles 
  • for macroclemys temminckii → betewen 24.5 and 27 degrees C, more than 50% are male, higher than that majority female
  • for trachemys scripta, below 28, 100% male 
  • alligator has a similar curve but at different temperatures 
  • with climate change, if temperature increases 2 degrees, huge impact on ratio of males to females 

16

What is environmental sex determination (ESD)?

  • occurs in most turtles and all crocodilians 
  • incubation temperature of eggs in critical time window → sex 
  • small change can have huge effect on sex ratios 
  • primarily controlled by modifying oestrogen production 
  • male temp → inhibits aromatase gene → testicular development 
  • female temp → aromatase gene → oestrogen → ovarian development 

17

How is sex determined in fish?

  • over 32,000 types of species 
  • two type of sex determination systems - GSD and ESD

18

What is fish sex reversal?

  • many fish are serial hermaphrodites
    • juvenile → male → female 
    • juvenile → female → male 
  • which pathway is better in terms of reproductive strategy?
    • female to male 
  • sex changed
    • colouration
    • behaviour
    • gonadal sex
    • nemo?
      • clown fish
      • dominant female and nondominant male and undifferentiated
      • remove dominant female and the male becomes female 

19

What is medaka fish sex differentiation?

  • GSD XX XY (DMY)
  • DMY → foetal testis → Dmrt1 → adult testis 

20

How is sex determined in drosophila?

  • the ratio of X chromosomes : autosomes determines sex
  • (A)X:A ration = 1.0 = female
  • = 0.5 = male 

21

What is the mechanism for sex determination in drosophila?

  • female
    • primary signal: 1.0 
    • key gene: SXL (active)
    • subordinate control genes: TRA (active) 
    • TRA-2 
    • double-switch: DSX
    • female
  • male
    • primary signal: 0.5
    • key gene: SXL (inactive splice) 
    • subordinate control genes: TRA (inactive splice) 
    • double-switch: DSX
  • DSX is alternatively spliced 

22

How is sex determined in C. elegans?

  • XX hermaphrodite: both ovary and testes 
  • XO male: testis only  
  • the primary sex determination depends on the ratio of X chromosome to autosomes same as drosophila 

23

What is the mechanism of sex determination in C. elegans?

  • master sex switch gene: xol-1 
    • on in X:A = 0.5
    • off in X:A = 1.0 
  • DM domain transcription factor:
    • mab3: on if xol-1 
    • male 

24

In summary:

  • conserved sox9 in vertebrates
    • XX/XY: most mammals SRY, medaka fish DMY 
    • ZZ/ZW: chickens dmrt1 
    • temperature: many species
    • all lead to production of SOX9 → sertoli cell differentiation → testis 
  • Dmrt1: DSX and mab-3 related transcript 1
    • mammals
      • signal: dominant Y → SRY-mediated regulation of gonad development, hormones → Dmrt1 (key male target gene) 
    • drosophila 
      • X:A ratio → cascade of regulated mRNA splicing → Dsx
    •  c elegans 
      • X:A ratio → secreted ligand-membrane receptor pathway → mab-3 
  • underlying genetic controls highly conserved 
  • Y determines gonadal sex in most mammals 
  • environments can stimulate sex differentiation 
  • X:A ratio determines sex in drosophila and C. elegans 
  • sex determining switch is highly variable across species