Flashcards in 10/08 - Sex Determination Deck (60)
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)
What proteins appear essential in inducing formation of primordial germ cells
Bmp4 & Bmp8b
What is the earliest known marker in the origin of germ cells?
TNAP - non-specific tissue alkaline phosphatase
What effect does TNAP KnockOut have on germ cell formation
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)
What processes begin in folliculogenesis?
Embryogenesis and fertilization
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
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.
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
- Autosomal dominant
- 46, XY sex reversal
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
What happens when you knockout SF1 in mice?
- Die before postnatal day 8
- male and female had internal FEMALE genitalia
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
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.
Why are streak gonads streaks?
- Because there are no germ cells inside
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
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
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
What happens when you add SRY to females?
Will have male genitalia
46, XY females
Due to Y chromosome deletion from X-Y interchange
Y-autosome translocations possible but rare
Mostly in the HMG box
Only 10-20% XY females have Sry mutations
Is SRY the only sex determining gene?
No; but it is the only one on the Y chromosome
- 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
What happens when you add SOX9 to female
- will lead to male phenotype
- Also known as MIS, is a member of the TGF beta family.
- Secreted by Sertoli Cells/Granulosa cells
- Causes regression of Mullerian derivatives
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.
What do we know about female development
- Very little
- Only two genes have been identified
- DAX1 not really involved
- Wnt4 = weak association
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.
Does knocking out Ahch affect female development in mice?
Wnt4 mouse KO
Lacks mullerian structures (uterus, upper vagina, fallopian tubes)
Germ cells are lacking
Testosterone biosynthesis activated in females
WNT4 mutant humans are masculinized
No uterus, no fallopian tubes
Ovaries of normal size
Aplastic right kidney
Elevated levels of androstenedione, testosterone, DHEAS