Sexual Differentiation Notes

Reproductive tract and differentiation

Determination of gender

Gender determination relies on three things

-Genotypic sex which determines gonadal sex which determines phenotypic sex- this becomes fully established at puberty

a) Chromsomal sex/Genotypic sex- correct chromosomal complement

-XX female, X0 Female (infertile) Turners: (underdeveloped ovaries, no menstruation, widely spaced nipples and short neck), XY Male, XXY Male (infertile)- Klienfelter’s syndrome (Poor beard growth, breast development, female fat distribution, under developed testes and reduced muscle strength) ,

-Factor involved in male development is the testis determining factor: the SRY Gene in the short arm of the Y chromosome-codes for a transcription factor- primary sex determination

-When this transcription factor is expressed in somatic support cells of the indifferent gonad-male development is triggered – upregulates testis specific genes/represses ovarian genes

-If SRY is absent somatic support cells will differentiate into ovarian follicle cells that envelop germ cells

Evidence of the importance of SRY

--The pseudo-autosomal region of the X and Y allow crossing and segregation in meiosis-SRY is close -Translocation of the SRY gene to the X chromosome can result in a XX chromosome complement in a phenotypic male, XY karotype in phenotypic female

-Evidence: Trasngenic mice with extracopies of the SRY gene-offspring develop as phenotypic males- develop as testes and male internal and external genitalia but are infertile as male germ cells don’t survive in an XX environment

-This led to the idea that females are the default pathway but it is found there are certain genes needed for female development such as DAX-1 which is needed for ovary development-DAX1 duplication in XY hormones causes sex reversal but in mice does not cause ovary formation

b) Gonadal sex - Functional testis/ ovary containing germ cells

-Gonads develop as a ridge on the medial aspect of intermediate mass mesoderm in the region of the mesonephros, failure of the gonadal ridge to develop produces an agonadal state. Once the ridge is formed it descends and becomes more compact and lies inferior to the kidney-gubernaculum-forms the round ligament in females

-Key genes involved in the formation of the gonadal ridge are Wilms tumour gene (WT1), Steroidogenic factor 1 (SFT), LIM1 or LHX9 : KO of genes-no gonads. These genes act upstream of the SRY and whithough gonadal formation subsequent phenotypic development will be female

-When gonadal ridge forms, no difference between male and female.

ii) In the gonad GERM cells are associated with somatic cells

-Primordial Germ cells that originate from epiblast, shown through fate mapping, develop in the extraembryonic membrane-yolk sac—distinctive pale cytoplasm, ovoid shape

-Primordial germ cells then migrate by ameboid movement from yolk sac to the wall of the gut tube- from the gut tube via the mesentery of the gut to the dorsal body wall- lie in the gonadal ridge-primordial germ cells proliferate during their migration- BMP2,4,8 are key for successful migration- mis-directed primordial cells during migration may develop into teratomas.

-When primordial germ cells arrive in presumptive gonad region- differentiation of the gonadal ridge occurs-In males germ cells are not necessary for the initial formation of testis tubules-mouse models in which germ cells don’t reach the gonadal ridge still have testis like structures-Evidence: Steel factor is a growth factor which is a ligand for c-kit tyrosine kinase receptor-this is essential in the survival of the grem cells-deletion of the the steel factor/receptor- there are no primarodial germ cells

Males: Development of the primitive testis

The primordial germ cells, prospermatogonia migrate and become embedded into the cortex of the gonad-proliferation- and forms primitive sex cords of the medulla. At Puberty primitive sex cords become hollowed out and develop into seminiferous tubules. The cells surrounding the primordial germ cells differentiate into SERTOLI cells initiated by expression of SRY.

Rete testis: system of thin interconnected tubules that develop in the dorsal part of the gonad, they drain the seminiferous tubules- contents of the rete testis flow into efferent ductules- these develop from adjoining tubules of mesonephros

-In the interstitial mesoderm cluster of Leydig cells differentiate from mesonephric mesenchymal cells recruited by pre-Sertoli cells, Leydig cells are endocrine cells that produce steroid hormone – Testosterone

Females: in the absence of SRY, causes sex cords to dissociate so that primordial germ cells are in nests forming primordial follicles. Abscence of SRY causes mesodermal gonadal cells to differentiate into granulosa cells. Even in the abscence of an ovary and its hormones- development of reproductive tract and external gentitalia

Meiosis commences then arrests in the fetus. Primordial cells develop but undergo atresia until puberty

Females- no SERTOLI cells so the mesodermal cells become the granulose cells which surround oocytes

-Normal gonadal differentiation produces a OVARY in females and a TESTIS in the male.

-Female pattern can be described as the default pathway but genes essential to the formation of an ovary (WNT-4)

-GONADS are formed before and control the development of the internal and external genitalia.

c) Phenotypic sex - possesses the correct internal and external anatomical male and female genitalia

i) Internal genitalia

-Indifferent stage in both sexes a paramesonephric/Mullerian duct (signalling molecule Wnt4 is key for its development), closely associated with the mesonephric/Wolffian duct is formed. Key...

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