Sex: Development and Gametes Flashcards

1
Q

What are primordial germ cells and how do they allow for gonadal development?

A
  • Arise at the base of the allantois and migrate to genital ridges
  • Develop into either testes or ovaries (sry gene causes differentiation to male)
  • Differentiate into either supporting cells, steroidogenic cells or germ cells.
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2
Q

Name the 4 genes involved in sex determination in an embryo

A

Sry - On Y chromosomes
Sox9 - maintains Sertoli cells; activates MIH
Dax1 - inhibits sox9/MIH
MIH - removes Mullerian duct
Sf1
Wt4

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3
Q

Give examples of how male sex is determined across species:

A

Active induction by sry gene (mammals):
- Male development active; female passive

Dose dependent on male gene:
- Birds (M = ZZ; F = ZW) where higher dose of Dmrt1 gene on Z in males induces development.

Temperature determined:
- Reptiles have no sex chromosomes
- Turtles (>32˚ C = female <28˚ C = male) due to temperature sensitive aromatase affecting testosterone/oestrogen balance

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4
Q

Explain some chromosomal disorders in humans:

A

Turner’s syndrome:
- XO producing infertile female (crossing over inhibited)

Klinefelter’s syndrome:
- XXY producing infertile male
- Slightly feminine physique and breast tissue

Guevedoces ‘penis at twelve’:
- XY but appear female until second surge of testosterone at puberty
- Due to alpha-reductase deficiency (testosterone not converted to dihydrotestosterone)

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5
Q

What is the evidence for bi-potential gonadal sex early in embryonic development?

A
  • Initially both the Wolffian duct (male) and mullerian duct (female) form.
  • Castrated male ends up with both ducts (even with androgens)
  • Mullerian duct disappears only if MIH present (male MIH knockout results in both ducts maintained).
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6
Q

How is the Wolffian duct selected for in males?

A
  • Sertoli cells secrete and respond to sry gene (+ve feedback)
  • Activates MIH causes degradation of mullerian duct.
  • Wolffian duct kep due to androgens and leydig cells
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7
Q

Which genes and molecules are involved in selecting for the wolffian duct in males?

A
  • Sry suppresses dax1 expression (so dax1 inhibits sox9 less)
  • Sox9 maintains sertoli cells and activates mullerian inhibiting hormone (MIH)
  • Causes atrophy of mullerian duct
  • Wolffian duct kept due to leydig cells and androgens
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8
Q

Why do females only have a mullerian duct?

A

Female development passive:
- Dax1 active which inhibits sox9 activity
- Suppresses androgen production (e.g. wnt4)
- Wolffian duct dissipates by neglect
- Mullerian ducts become fallopian tubes

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9
Q

What are the different ways that sex can be identified?

A
  • Chromosomal sex
  • Brain sex (behaviour and ovulation)
  • Phenotypic sex
  • Gonadal sex
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10
Q

Give experimental evidence for brain masculinisation:

A

Androgens converted to oestrogen in brain (by aromatase) to have effect in male:
- Prevents ovaries from undergoing cyclic ovulation
- Male with removed testes and inserted ovaries will have ovarian cycles if changed at birth but not if done later.

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11
Q

What are the functions of Sertoli cells (during development and reproduction)?
What about leydig cells?

A

Sertoli cells
During development:
- Sexual differentiation (secrete sry)
- Create blood/testes barrier

For spermatogenesis:
- Mechanical and nutritional support
- Contain androgen binding protein for HPG axis

Leydig cells
- Produce testosterone

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12
Q

Describe the stages of spermatogenesis:

A
  1. A0 spermatogonia self-renew and divide by mitosis
  2. Become spermatocytes (4n = large cells) and undergo mitosis
  3. Haploid spermatids formed
  4. Spermiogenesis occurs
    - Acrosome, flagella and mitochondrial sheath formed
    - Residual cytoplasm removed
    - Histones replaced by protamines
  5. Mature spermatozoa formed
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13
Q

How is sperm production kept continuous?

A
  • Renewal of A0 spermatogonia (every 64 days)

Spermatogenic cycle:
- Re-initiated after 1/4 of total time (e.g. after 16 days in humans)

Spermatogenic wave:
- Progressive changing of cell associations to a particular spermatogenic cycle

Reduce damage to sperm:
- Temperature controlled
- Counter current exchange
- External
- Extra sweat glands

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14
Q

How does the HPG axis stimulate sperm production?

A

GnRH stimulates gonadotrophs in pituitary to produce FSH and LH:
- LH stimulates testosterone production (binds LHR on Leydig). Therefore regulates initiation of spermatogenesis.
- FSH acts on Sertoli cells

Negative feedback loops:
- Testosterone produced by Leydig cells inhibits GnRH and LH/FSH production
- Inhibin from Sertoli cells inhibits FSH secretion from pituitary

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15
Q

How does FSH stimulate Sertoli cells?

A
  • Increased protein synthesis
  • Upregulates testosterone receptor expression and testicular fluid
  • Increases inhibin secretion
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16
Q

What changes do sperm undergo through the epididymis?

A

Passive travel through (using smooth muscle and cilia).

Increased fertilisation capability:
- Structural changes (removal of cytoplasmic droplet and head sculpting)
- Glycoprotein coat formed of EPPIN (peptidase inhibitor) and lipocalins (prevents premature acrosome release)

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17
Q

What are the properties and contents of seminal fluid?

A
  • pH 7.2-7.8 (combat acidic uterus)
  • Salts and ions
  • Coagulating enzymes; proteolytic enzymes; mucus
  • Roughly 280million sperm per ejaculate (only 200 make it to oocyte)
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18
Q

How do erection and ejaculation occur? how does Viagra help?

A

Parasympathetic control:
- ACh release causing cGMP synthesis, NO synthesis and smooth muscle relaxation
- Increased blood flow to sinuses (corpus cavernosa and spongiosum)
- Viagra: inhibits PDE type 5, maintaining cGMP levels

Ejaculation: sympathetic control:
- Smooth muscle contraction in vans deferens and accessory gland

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19
Q

Why do the majority of sperm not make it to the egg?

A
  • Female defences: mucus, monocytes, peroxide production, low pH
  • Sperm competition (within male and intraspecific)
  • Flowback
  • De-coagulation of sperm
  • Oviduct fluid movements (uterine cilia and oviduct sphincter movements due to oxytocin/prostaglandins)
20
Q

How do sperm increase their chance of successful fertilisation?

A

Navigation:
- Oviduct fluid movement
- Sperm naturally orient into flow direction (need these movements to navigate)
- Chemotropic factors from ovum

Timing – only 24hr window when ovum is viable:
- Sperm are stored in oviductal isthmus to increase chance (duration species dependent)
- Can result in “non-paternity”/discordant twins/mixed litter

21
Q

What competition do sperm face to reach oocyte?

A

Within ejaculate:
- Fastest swimmer wins (5mm/min)

Between males:
- Last sperm precedent
- Active killing by other seminal fluid and intentional sperm polymorphism (to block later sperm)
- Copulatory plug formed after successful fertilisation

22
Q

Describe capacitation:

A

Biochemical changes to allow for sperm to fertilise egg:
- Seminal plasma removed
- Glycosaminoglycans and cholesterol removed including CRISP-1(prevents premature acrosome reaction by blocking CatSper channel)
- Increased Ca2+ sensitivity (CatSper sensitivity increased by progesterone)

23
Q

Describe the process of fertilisation:

A

Penetration:
- Acrosome reaction occurs on contact with ZP3. ZP2 facilitates passage through.
- Acrosome reaction = specialised exocytosis (releases acrosin, hyaluronidase and matrix materialise protease 2 (MMP2))

Changes to Ovum after fertilisation:
- Completion of meiosis II
- Ca2+ wave resulting in cortical granule release and cortical reaction (ZP hardening)

24
Q

Describe the stages of oogenesis:

A

Before birth:
1. Oogonia (germ cells) undergo mitosis
2. Millions of primary oocytes arrest in meiosis I

After birth: most oocytes undergo atresia loss (death) - Some form pre-antral follicles with a ZP
- Develop into Graafian follicles (responsive to pituitary hormones)

At sexual maturity:
1. Undergoes meiosis I forming a secondary oocyte
2. Arrest in meiosis II (close to ovulation)
3. LH surge induces ovulation

25
Q

Describe the stages of follicular development prior to ovulation:

A
  1. Primordial follicle stage (squamous granulosa cells surrounding oocyte)
  2. Primary follicle stage (cuboidal granulosa cells)
  3. Pre-antral follicle
    (More cuboidal granulosa cell layers and thecal cells become associated)
  4. Graafian follicle forms containing an antrum and oocyte
  5. Follicular rupture at ovulation (with cumulus oocyte complex)
26
Q

What roles do granulosa cells have?

A

Production of oestrogen

In follicular development:
- Stop spontaneous activation (inhibit using cyclic AMP)
- Protect and provide oocyte with nutrients

27
Q

Detail the stages of ovulation:

A
  1. Several ova begin development – all degenerate but one
  2. Large follicle – pushes itself to the side
  3. Stigma process of oocyte contacts follicular fimbriae to capture the egg
  4. Cilia and muscular cells gently push egg along fallopian tube.
  5. Follicle develops into a corpus luteum after ovum release

Number of oocytes ovulated = monovular or polyovular

Number of offspring in pregnancy = monotocous/polytocous

28
Q

What effects does LH have?

A

Stimulates Theca cells to produce testosterone:

  • Granulosa cells convert testosterone to oestrogen (aromatase activity)
  • Induces completion of first meiotic division
  • Withdrawal of granuloma cell processes
  • Formation of cortical granules
  • Increase in collagenase activity (particularly in stigma region of follicle)
29
Q

What are the feedback loops controlling the hypothalamic-pituitary-gonadal axis?

A

FSH stimulates granulosa cells –> oestrogen and inhibin –> inhibits HPG axis

Low oestrogen acts on kisspeptin neurons in the arcuate population to inhibit hypothalamus (-ve feedback)

High oestrogen acts on neurons in anteroventral periventricular region to excite hypothalamus (+ve feedback)

30
Q

Contrast spermatogenesis and oogenesis:

A

Temporal:
- Continuous sperm production and maturation vs. cyclic for oocyte
- Concurrent production of androgens and sperm vs. cyclic production of ova and steroids (complex pattern)
- Meiosis initiated at puberty vs. before birth
- Spermatogenesis continues throughout life vs. stops at menopause

Quantitative:
- Infinite number of gametes from stem cell renew vs. no self-renewal (after birth)
- Few oocytes released each cycle vs. millions on ejaculation
- 1 primary spermatocyte = 4 spermatozoa vs. 1 primary oocyte = 1 ovum

31
Q

Describe the progression of hormones during the menstrual cycle:

A

Follicular (proliferative) phase followed by luteal (secretory) phase:
1. Rise in oestrogen causing follicular maturation
2. LH surge before ovulation
(induces oestrus behaviour)
3. Progesterone surge to maintain uterine lining from the corpus luteum
(oestrogen & progesterone thicken uterus)
4. Fall in progesterone allows rise in oestrogen to restart cycle

32
Q

Describe control of the corpus luteum in sheep:

A
  • C.L produces in oxytocin to stimulate uterus
  • Uterus produces luteolytic factor prostaglandin F2α
    (shown as hysterectomy stops C.L breakdown)
  • Prostaglandin F2α inhibited by foetus in case of pregnancy to maintain progesterone
33
Q

How is C.L. breakdown prevented in a pregnant mouse?

A
  • Mechanical stimulation of cervix during mating decreases dopamine and thus allows prolactin release from ant.pituitary (shown as still occurs after mating with infertile male)
  • Prolactin is a luteotropic factor
34
Q

Suggest 4 factors which affect ovulation and behaviour:

A

Hormonal control:
- Due to cycle
- Due to signals in semen (nerve growth factor (NGF) in semen of camels)

Mechanical stimulation:
- In rats (decreased dopamine)
- Others: mechanical stimulation of cervix = more GnRH = more LH and FSH from Ant.P = ovulation

Pheromones:
- E.g. pig hormone androstenone that changes female behaviour (makes sow stay still)

Behavioural changes
- Female camels lie down to allow mating

35
Q

What changes occur in the uterus to prepare for mating?

A

During high oestrogen period:
- Keratinisation in vagina to protect from mating
- Cervical mucus is thinner to facilitate sperm entry

36
Q

What changes occur in the uterus to prepare for implantation?

A
  • Constricted cervical tone (reduce sperm entry) and pinopodes activate
  • Thickening of endometrium (gland formation)
  • Reduction in microvilli
  • Mucin expression decreases
  • Decidualisation occurs
37
Q

What are some ways manipulate ovarian cycles?

A

Steroidal contraceptives (high dose progesterone +/- low oestrogen dose):
- Inhibition of ovulation by negative feedback

Induction of synchronous cycling of animals:
- Progesterone vaginal sponges (removed together to induce ovulation at similar time)
- Prostaglandin analogues to induce luteolysis (e.g. prostaglandin F2α)

38
Q

What are some male contraceptive mechanisms?

A

Hormonal:
- Long acting progesterone to suppress GnRH

Non hormonal:
- Block vas deferens (allows solute movement but not sperm)
- Catch sperm using anti-EPPIN (inhibit sperm motility)
- ‘Clean sheet pill’ inhibits smooth muscle contraction of vas deferens

39
Q

What are some factors which affect fertility?

A
  • Age (puberty/menopause)
  • Genetic factors
  • Pathological factors
  • Environmental factors
  • Physiological factors
40
Q

What is the re-activation of HPG axis theory causing puberty?

A

Gonadostat theory: cells are less sensitive to sex hormones in adult life so LESS inhibited:
- Increased frequency and amplitude of GnRH pulses
- Decreased GABA and increased glutamate/kisspeptin
- Increased pulsatile release of LH and FSH

Evidence:
- Premature puberty cause when HPG activated early
- Reactivation of HPG axis still occurs in animals castrated straight after birth.

41
Q

What are some factors necessary for entry into puberty?

A
  • Normal genetic function (sry genes activated; functioning sex chromosomes)
  • Body mass must be over critical weight (47-55kg)
  • Nutrition: menses are metabolically expensive (first menarche decreased from 1850-1960)
42
Q

Name some pathological factors affecting male fertility:

A
  • Breakdown of blood-testes barrier – sperm autoantibodies can be raised
  • Cystic fibrosis: loss of vas deferens (due to thick mucus causing atrophy of tubules)
43
Q

How does seasonality affect fertility?

A

Photoperiod dependent in many animals:
- Melatonin interacts with hypothalamus to change GnRH secretion
- Melatonin produced in dark
- Short-day breeders (sheep) have melatonin activated GnRH neurons
- Long-day breeders (horses) have melatonin inhibited GnRH neurons (

44
Q

How does melatonin affect GnRH production in long-day breeders (e.g. horses)?

A

Suprachiasmatic nucleus detects day length and leads to melatonin production in dark: Acts on arcuate nucleus:
1. Pars tuberalis inhibited by melatonin (produce less TSH)
2. TSH stimulates ependymal cells to form T3 (T4 –> T3 using DIO2)
3. High T3 reduces GnRH production

45
Q

What are some physiological factors which affect fertility?

A

Lactation:
- Inhibits ovarian cycle by mechanical stimulation of mammary.
- Increased β-endorphin which naturally inhibits GnRH
- Reduced dopamine increases prolactin release which inhibits LH/FSH release
= Cessation of ovarian cycles
Evidence: !Kung tribe have a baby every 4 years

Implantation prevention:
- Prolactin inhibits oestrogen which is required for implantation
- A fertilised embryo cannot implant and is held in the uterus at the blastocyst stage in diapause.

Stress reduces fertility.

46
Q

How does oestrogen show local and systemic +ve feedback?

A

Local (ovary):
- Oestrogen stimulates granulosa cells
- Granulosa cells mature and increase their capacity for testosterone production (and therefore oestrogen)

Systemic (in hypothalamus):
- Switch between ARC and AVPV nucleus