W8L1 mon Sex Differentiation Flashcards
What is sex determination
- Sex determination: embryo makes decision to go down male/female development pathway
§ Genetic sex: chromosomal compliment
Ø Heterogametic: different sex chromosomes (birds – ZW = F, ZZ = M)
Ø In drosophila: dosage of X chromosome determines sex (fly – XX = F, X = M)
§ Somatic sex: differentiation of internal + external genital
§ Brain sex: brain patterns according to gonadal sex; behaviour + neuroendocrine
mammals unqiue characteristic in sex determination
: male + female embryos have identical indifferent gonads + external genitalia (bipotential system)
method of sex determination
- Temperature-dependent sex determination (TSD): incubation temperature of eggs determine sex, no sex chromosomes
- Genetic sex determination (GSD): XX/XY in mammals; ZW/ZZ in birds, some snakes
§ X:autosome ratio in insects (flies have no hormones, determined by no. of X chromosomes)
§ Mammals: SRY gene responsible for male sex determination + sits on Y chromosome (within pseudoautosomal region)
mammals sex chromosome
Ø Pseudoautosomal region = short region of sequence homology b/w sex chromosomes
Ø Abnormal recombination may cause XX males + XY females (SRY gene on wrong chromosome)
Ø XY: SRY gene activate SOX9 which induce testis formation, repress WNT4
Ø XX: absence of SRY; WNT4 represses male sex development
self fertilization method
- Parthenogenetic: female lays an egg which develops into a clone (insects, turkeys, reptiles)
- Hermaphroditic: contain male + female sex organs, able to produce clones
gonad formation
§ Gonads form on mesonephros (primitive kidney) + develop into testes (SRY present) or ovaries (no SRY)
Ø Eventually only gonad left in coelomic cavity + testes must descend/ovaries remain
§ Mullerian duct (paramesonephric): forms female urogenital tract
§ Wolffian duct (mesonephric): forms male urogenital tract
testis differentiation in mouse
SRY activation → SOX9 activation → multiple genes activation→ testis formation
Ø Proliferation of coelomic epithelium and blood vessel formation for male hormone production = masculinisation
Ø Male-specific vasculature – endothelial cells in-growing from mesonephros (needed for testis cord formation)
Ø Sertoli cells (<E11.5): anti-Mullerian hormone (AMH) removes female pathway, germ cells migrate into gonad =
forms of testis cords (seminiferous tubules after birth) (E12.5) + enter mitotic arrest
Ø Leydig cells (~E13): androgens
ovary differentiation in mouse
§ Ovary differentiation (mouse): PGCs migrate into developing ovary + enter meiotic arrest
Ø PGCs that migrate to the wrong place (medulla) apoptose
Ø Follicle cells (granulosa) probably form from coelomic epithelium
§ Supporting cells become Sertoli cells (SRY/Sox9) or granulosa cells (Ctnnb1/Foxl2)
§ Steroidogenic precursors become Leydig cells (release testosterone) or theca cells (release testosterone converted into oestrogen)
§ Germ cells go into mitotic arrest + produce spermatogonia or meiotic arrest to produce oogonia
Urogenital Development, alfred jost experiment on rabit
Ø Female foetus → ovaries removed → female adult
Ø Male foetus → testes removed before testosterone secretion → female adult (reproductive tract + brain)
importance of testis in male urogenital development
§ Intact testis required to develop a male urogenital tract
Ø Intact male: wolffian duct remains, Mullerian duct regresses
Ø Female/castrate: Mullerian duct remain, wolffian duct regresses
Ø Female with testosterone crystal implanted next to ovary: Mullerian duct + wolffian duct remain
§ Testosterone is not sufficient to remove Mullerian duct
Ø XY male: AMH regressed Mullerian duct + testosterone stimulated Wolffian duct
Ø XX female: Mullerian duct develops in absence of AMH (fallopian tube, uterus, cervix, upper 1/3 vagina) + regressing Wolffian Duct (no testosterone)
Male hormone
Male hormones: testosterone converted into 5a-dihydro-testosterone (DHT) to masculinise tissues
Ø In the brain, aromatase converts testosterone into oestrogen important for male-specific behaviours
Ø Penis patterning (erectile function) depends on DHT + oestrogen
genital tubercles (the embryonic precursor of the penis and clitoris)
Early embryos contain genital tubercles
Ø Males: presence of DHT = elongation of genital tubercle (forms glans of penis), genital folds fuse at midline (forms shaft of penis), scrotal swellings form scrotum
Ø Females: genital tubercle form clitoris, genital folds don’t fuse (form labia minora), labial swellings form labia majora
testes migration
§ Testes descend from abdomen to scrotum via inguinal canal
Ø Androgens, INSL3 + AMH from testes, CGRP from genitofemoral nerve
Ø External scrotal location = 2-3˚C cooler than in abdomen
Ø Cryptorchidism (failure to descend) = no sperm production, high risk of testicular cancer
Brain Patterning
-aromatase enzyme in many brain areas (only affects males during development)
* non-aromatisable androgens like DHT do not have same effect on brain as testosterone
* oestrogens masculinise brain
* anti-oestrogens can block some effects of T on brain sex
* effects via cell divisions in some cells and apoptosis in others location of the sexually dimorphic nucleus in the preoptic area (SDN POA) and the anteroventral- periventricular nucleus of the POA (AVPv-POA) of the rat
male SDN-POA > female (behaviour?)
male AVPv-SDN < female (LH surge?)
experiment on brain patterning
§ measuring LH surge + ER-beta in rat brain (AVPv-POA)
Ø Female treated with oestrogen at d1-10 after birth had brains similar to males + unable to ovulate or produce an LH surge
Ø Male castrated at birth equivalent to female brain
