10/08 - Sex Determination Flashcards Preview

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Flashcards in 10/08 - Sex Determination Deck (60)
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1

Origin of Germ Cells

- Drosophila and C. elegans egg polarity determines origin of germ cells (posterior end of the fertilized egg)
- Egg polarity not yet demonstrable in mammals
- In mammals, germ cells arise from proximal epiblast (embryonic ectoderm)

2

What proteins appear essential in inducing formation of primordial germ cells

Bmp4 & Bmp8b

3

What is the earliest known marker in the origin of germ cells?

TNAP - non-specific tissue alkaline phosphatase

4

What effect does TNAP KnockOut have on germ cell formation

No effect

5

Folliculogenesis

Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that enter the menstrual cycle.

Once the oocytes are rested in meiosis I; at stage called primordial follicle. You will recruit many oocytes of which only one will be ovulated (until menopause)

6

What processes begin in folliculogenesis?

Embryogenesis and fertilization

7

What is the default pathway? And how do we know this?

- Female pathway is the default
- We know this because of Alfred Jost's experiments with removing the ovaries and testes from rabbit fetuses. Both became female adult.
- In male fetus, the wolfian duct regressed and uterus, oviduct, and upper vagina formed

8

What actually causes sex determination?

- Y chromosome is a very gene poor region and the majority of genes involving sex determination are on autosomes; not the Y.

9

Human WT1 gene

- Wilms tumor suppressor/activator gene - regulates transcription
- Causes Frasier syndrome, Denys-Drash symdrome (Wilms tumor + pseudohermaphroditism
- Denys-Drash greater renal tumors risk
- Gonadal dysgenesis
- Gonadoblastoma
- Autosomal dominant
- 46, XY sex reversal

10

What happens when you knock out the WT1 gene in mice?

- Die between E13.5 and birth
- Fail to develop kidneys and gonads
- Heart, lung, and spleen also affected
- Mouse replicates human phenotype

11

What happens when you knockout SF1 in mice?

- Die before postnatal day 8
- male and female had internal FEMALE genitalia

12

What happens when you knockout SF1 in humans?

- phenotypic female
- karyotype XY
- high ACTH
- low cortisone
- low aldosterone
- laparoscopy showed streak gonads, normal mullerian (female) structures otherwise
- Estrogen and progesterone induced periods
- she lacks gonads and has adrenal hypoplasia

13

Describe the role of ACTH

ACTH: adrenal glands produce cortisol which provides negative feedback on pituitary gland which produces ACTH. If pituitary gland isn’t getting enough cortisol, the pituitary glad will jack up ACTH trying to get all the cortisol possible out of adrenal glands.

14

Why are streak gonads streaks?

- Because there are no germ cells inside

15

Describe the phenotype and etiology of 46,XX males

Phenotype: male external genitalia and testes, often well virilized, sterile
Etiology: X-Y interchange during paternal meiosis

16

What happens if you have an X and a Y chromosome with faulty recombination?

If you have X and Y chromosome (TDF = SRY gene) If there is a faulty recombination and SRY ends up on X chromosome; If this happens; the karyotype would be XY, but phenotypically female. This accounts for 46% of 46,XX males

17

SRY is TDF

- Expressed from E10.5 to E12.5 (immediately prior to seminiferous tubule appearance)
- Expressed in pre-Sertoli Cells
- Y linked inheritance
- Conserved in mammals

18

What happens when you add SRY to females?

Will have male genitalia

19

46, XY females

Sry negative:
Due to Y chromosome deletion from X-Y interchange
Y-autosome translocations possible but rare

Sry mutations:
Mostly in the HMG box
Only 10-20% XY females have Sry mutations

20

Is SRY the only sex determining gene?

No; but it is the only one on the Y chromosome

21

Human SOX9

- Mutations in SOX9 cause Campomelic Dysplasia (bone abnormalities)
- 46, XY sex reversal with ambiguous or female genitalia
- Death in neonatal period due to respiratory insufficiency
- SRY-related gene
- Autosomal dominant

BOWING OF THE BONES IS STRIKING IN THESE CASES

22

What happens when you add SOX9 to female

- will lead to male phenotype

23

Amh

- Also known as MIS, is a member of the TGF beta family.
- Secreted by Sertoli Cells/Granulosa cells
- Cryptoorchidism
- Causes regression of Mullerian derivatives

24

Amh/Amhr human mutations

Persistent Mullerian duct syndrome

Typically: male with uterus and fallopian tubes

Amh and its receptor have same phenotype

Mice Amh/Amhr KOs show similar phenotype

These men can be infertile, can also have problem with descent of their testes.

25

What do we know about female development

- Very little
- Only two genes have been identified
- DAX1 not really involved
- Wnt4 = weak association

26

AHC (DAX-1, Nr0b1, Chr. Xp21.3)

Nuclear hormone receptor with DNA binding domain
Deletions cause congenital adrenal hypoplasia, and hypogonadism
Expressed in Sertoli cells
Duplication of Xp21 (XY individuals) develop as females, external genitalia, impaired testes by histology (DSS- dosage sensitive)
Female fertility is unaffected
Maybe duplication of gene drives female development? But when you knock out Ahch gene; you find that female development is not affected.

27

Does knocking out Ahch affect female development in mice?

No

28

Wnt4 mouse KO

Lacks mullerian structures (uterus, upper vagina, fallopian tubes)

Germ cells are lacking

Testosterone biosynthesis activated in females

29

WNT4 mutant humans are masculinized

Mayer-Rokitansky-Kuster-Hauser syndrome
Primary amenorrhea
Short vagina
No uterus, no fallopian tubes
Ovaries of normal size
Aplastic right kidney
Elevated levels of androstenedione, testosterone, DHEAS

30

GENITAL AMBIGUITY


True hermaphroditism (46, XX ovotesticular disorder of sex development)

Female pseudohermaphroditism (46, XX disorders of sex development)

Male pseudohermaphroditism (46, XY disorders of sex develpoment)