Sex Determination In Mammals Flashcards
Describe the role of wnt4 in sex determination and where is it initially expressed?
Partial anti-testis gene
Initially expressed indifferent gonads of both sexes
Female specific
What occurred in wnt4 XX knockout gonads?
Showed aspects of testis differentiation and express SOX9, testosterone
What molecules enhance B-catenin production?
R-spondin1 and wnt4
What is B-catenin and its role?
A key pro-ovarian/ anti-testis signalling molecules
Initiates ovarian development by activating gene involved in granulosa cell differentiation
Prevents the accumulation of sox9
Describe what happens when B-catenin activates the expression of TAII105?
B-catenin activates expression of TAFII105
* TAF (TBP-associated factor) binds TBP (TATA-binding protein) enabling TFIID to interact with the promoter and recruit RNA polymerase II. TAFII105 replaces the ubiquitous TAFII130.
* Enables expression of multiple gene requires for folliculogenesis and oocyte maturation- TAFII105 knockout females are infertile
What happen in the absence of TAFII105?
Ovarian-specific gene are down regulated in the absence of TAFII105
* Wnt signalling (+FOXI2) is required for follistatin expression
* Follistatin is required for granulosa development
* XX mice lacking follistatin in the developing gonad undergo patial sex-reversal, forming testis-like structures
Overall what controls gonadal fate?
Gonadal fate is controlled by antagonism between FGF9/Sox9 and wnt 4/ b- catenin
* FGF9 XY knockout shows meal to female sex reversal; cells cannot maintain sox9 expression nor establish
* FGF0 stabilises sox9 expression- supersets wnt4 expression, securing male fate for gonad
* wnt4 xx Knockout gonads show some aspects o testis differentiation, sox9 and FGF9 upregulates
* Wnt4 opposes the male pathway by repressing sox9 and FG9 expression; synergises with RSPO1 to enhance b-catenin production, activating TAFII105 and female fate for gonad
What is secondary sex determination?
Development of the male o female sexual phenotype- other sexually dimorphic characteristics, including internal and external genitalia- everything outside the gonads
What did Alfred jost discover?
In male- when testes removes- ducts look like the female - Müllerian ducts maintained- wollfian duct not present
* Present of testes required to form the rest of male body pattern
What role does testosterone play?
Supports growth of male structures and hormone that suppress female development
Showed treatments of testosterone maintained wolffian ducts and development of male genetically
But no cell death of mullerian ducts
Desrcibe hormone control for testis?
Hormones from the testis control development of male internal and external genitalia
* Sertoli cells differentiate first, induce leydig cells to differential
* Sertoli cells secrete mullerian inhibitory substance (MIS)/ anti- mullerian hormone
* TGF-B signals that causes Müllerian duct degeneration
* Leydig cells secrete testosterone
* Steroid that masculinerises emus and promotes wolffian ducts development
What is androgen insensitivity hormone
Androgen insensitivity syndrome (XY)
* Mutation in androgen receptor
* Testes produce testosterone as normal but cells cannot respond to testosterone
* Wolffian ducts degenerate
* External genitalia appear femal (testes do not descend)
* MIS leads to Müllerian duct degeneration
* Oestrogen produced by the adrenal gland feminises the phenotype
Describe hormone control of ovary development?
Hormones from the ovary control development of female internal and external genitalia
* Granulosa cells differentiate first, then induce theca cells
* Follicles secrete oestrogen (thecal cell produce androstendione that is converted to oestrogen by a granulosa enzyme, aromatase)
* Steroidogenic that feminises fetus and promotes ovarian development
* In the absence of MIS, Müllerian duct develops
* Wolffian ducts degernate as low testosterone levels are low
What occurs in the pregonadal genital ridge.
In the pregonadal genital ridge (very start ), gene expression is common to both seces
* Genes including s1 ihx9 and wt1 are needed for early growth and cell survival in the developing gonads
* XX and XY knockouts initiate gonads development but the primordia subsequently regress
* Embryos develop as phenotypic females, owing to absence of gonads
* Molecular confirmation of hosts embryo logical experiments
* Genes expressed in the pregonadal state can have later roles in male/ male sex determination
What is steroidogenic factor 1. What does it do?
Steroidogenic factor 1 (sf1) cooperates with sry to upregulates sox9 expression in the XY gonads
SF1 binds TES and activates sox9 expression in both sexes
Sry cooperates with SF1 to upregulates sox9 expression in XY gonads only
Sox9 binds its own enhancer, replacing sry and interacting directly with sf1. SF1 and sox9 recruit each other to additional binding sites.
SF1 activates expression of masculining hormones
* SF1 downregulated in the X genital ridge but stays on in the XY developing testis
* SF1 masculinises the leydig and Sertoli cells
* In Sertoli cells, sf1 and sox9 work together to induce transcription of AMHIMIS
* In leydig cells, sf1 activates transcription of enzymes that synthesis testosterone
What is sexual dimorphism
systematic differences in form between individuals of different sexes from one species
What is sex determination?
how genes and hormones interact during development to produce two alternative phenotypes
At what week do the bipotent gonads appear and wolffian and müllerian ducts become present
week 4
At what week do the gonads form testes or ovaries
week 7
In males, what do the wolffian ducts become
vas deferens
In females, what do the müllerian ducts become
oviduct
What are the supporting cells in testis and ovaries
testis = sertoli
ovary = granulosa
What are teh steroidogenic cells in testis and ovary
testis = leydig
ovary = theca
What is primary sex determination
sex-specific supporting cells differentiate first, through transcriptional regulation and paracrine/autocrine signalling, then induce differentiation of the steroidogenic cells
What is secondary sex determination
leydig/theca cells shape the rest of the sex-specific phenotype. Secrete hormones to alter secondary determination (everything outside of the gonads, which have formed through primary sex determination)
What directs the somatic cells of the gonad to develop into testes
presence of testes determining factor on the Y chromosome
Where is the TDF located?
Yp11.3 on Y chromosome
What is the male determining gene cloned from Yp11.3
Sry
What do Sry-expressing cells differentiate into
sertoli cells
What does Sry do?
binds to DNA and activated genes involved in testis development
What genes other than Sry are needed for male determination
sox9
MIS
P40-aromatase
What synergies with Wnt4 to enhance beta catenin production
R-spondin1
What must be repressed in males for testis to develop
wnt4
What is FGF9 and where is it expressed
becomes male specific after sry expression, promoted by sox9 expression and emulates proliferation of precursor cells. stabilises sox9 and repressed wnt4, secures male fate for gonad
What does Sry activate the expression of
sox9
