Determinants of Sexual Differentiation

Genetic Sex is determined at the moment of conception (46XY, 46XX, etc.)

Gonadal Sex is determined after conception in three different stages corresponding to structures.

(1) Gonads – factories churning out gametes – develop from common anlage

undifferentiated gonad appears at week 5 when the gonadal ridge develops from mesenchyme

(2) Internal Structures – plumbing – develop from distinct anlage for each gender

genetic influence on sexual differentiation is greatest around the 7^th week of gestation

Male: If a normal Y chromosome is present the gonadal ridge differentiates into testes

Sertoli cells make Mullerian Inhibitory Substance (MIS) Þ causing the ipsolateral Mullerian ducts to regress.

Leydig cells make testosterone Þ induces Wolffian Ducts to develop into internal structures (pipes)

also epididymis, etc.

Female: the default pathway; in the absense of testosterone, the undifferentiated gonads becomes ovaries

Wolffian ducts regress and Mullerian ducts develop into internal structures (pipes)
also fallopian tubes, vagina, uterus, etc.

(3) External Structures – coupling devices – develop from common anlage as do Gonads – see diagram below:

Male: requires two things; absense of either leads to female genitalia

Female: default pathway (as in Internal Structures)

Y Chromosome – determines pathway of sexual development

Y chromosome contains the SRY gene (contains Testis Determining Factor, TDF)

SRY gene product is a member of the HMG family of DNA-bending transcription factors: therefore regulates genes

Males can be 46 XX, with SRY on one of their X chromosomes–how does it happen?

normal meiotic crossover occurs between the tip of X and Y chromosomes (thus it is called the "pseudoautosomal region")
abnormal crossover can occur below the SRY gene, resulting in the transfer of TDF to an X chromosome
expression of the SRY on X chromosome results in testicular development and differentiation

Other Genes that Contribute to Sexual Differentiation

Z gene – model developed to explain 46 XX males without SRY

active repressor of testis development; SRY represses this gene (a repressor of a repressor); loss of Z gene will result in testis development even if neither a Y chromosome nor an SRY gene is present

DSS (Dosage Sensitive Sex Reversal)–fits the Z-gene pattern; if duplicated, will be female even in presence of SRY

DSS gene is located on Xp21, and may be the gene DAX1

in presence of SRY, DSS is suppressed Þ male; in absence of SRY, DAX1 is not suppressed Þ female

in presence of SRY with duplication of Xp21 on same chromosome, SRY repression is overcome Þ female

in presence of SRY and multiple X chromosomes (resulting in multiple copies of DSS), SRY is not overcome due to X inactivation of the extra X chromosomes Þ male

contradicts the dogma of ovary as default; suggests rather that there is an "Ovary Determining Region" that prevents testicular development

SOX 9 – on 17q24; expressed in Sertoli cells – if mutated, will be female even in presence of SRY

mutations Þ camplomelic skeletal dysplasia (often lethal) – 75% of 46XY patients with this disease are female

WT1 – on 11p; deletion Þ Denys-Drash Syndrome (Ý risk of Wilms Tumor, also renal, gonadal, genital malformations)

Steroidogenic factor 1 (SF1) – autosomal gene expressed on Sertoli cells, ovary, testis

10q25 and 9p24 are associated with sex reversal

Sexual Ambiguity – tests involve chromosome analysis or dye study to see internal genitalia