Sex Development 2

Question 1

Describe the role of SF1.

Answer 1

• One of the earliest acting genes in reproductive tract development
• Affects all three levels of the hypothalamic-pituitary-gonadal axis
• Regulates other genes:
  
  • ACTH receptor
  • LH
  • AMH
• Mutations suggest dosage effects
  
  • homozygous - gonadal dysgenesis and adrenal insufficiency
  • heterozygous - gonadal dysgenesis without adrenal insufficiency

Question 2

Describe the role of SRY.

Answer 2

• Testes-determining factor
• Specific roles
  
  • induces Sertoli cell differentiation
  • migration of mesonephric cells into the genital ridge
  • proliferation of cells in the genital ridge
  • male-specific vasculature
• Sex reversal in 46, XX males with SRY and 46, XY females without SRY

Question 3

Describe the role of SOX9.

Answer 3

• Sex-determining factor
  
  • upregulated after SRY
  • expressed in Sertolic cells
  • regulates AMH
• Induces chondrogenesis
• Haploinsufficiency leads to XY gonadal dysgenesis (male to female sex reversal and campomelic dysplasia

Question 4

Describe the role of DAXI.

Answer 4

• Dose-sensitive sex reversal
• Adrenal Hypoplasia Congenita Locus on Chromosome X, Gene I
• Expressed in:
  
  • hypothalamus
  • pituitary
  • testis
  • adrenal cortex
  • ovary
• Human duplication → 46, XY sex reversal
• Human deletion:
  
  • adrenal hypoplasia congenita
  • hypogonadotropic hypogonadism
  • may also have impaired spermatogenesis

Question 5

Describe the role of WNT 4.**

Answer 5

• Expressed early and involved in gonad development
• Balanced opposition model
  
  • Female
    
    • mullerian duct formation
    • maintain oocytes in cortex
    • suppress Leydig cell development in ovary
  • Male
    
    • proper testis vasculature
    • organization of sex cords
• Heterozygous human WNT4 mutations seen in 46, XX females with Mayer-Rokitansky-Kuster-Hauser syndrome (absent mullerian structures)
  
  • mild virilization and increased androgen concentrations

Question 6

Describe the role of AMH.

Answer 6

• Antimullerian hormone
• Produced by Sertoli cells
• Regulated by SF1 and SOX9
• Causes regression of mullerian strucutres
• Paracrine effects - AMH from testis causes regression on ipsilateral side
• Also produced in:
  
  • late gestation
  • after birth
  • adulthood
• Mutation found in 46, XY individuals with persistent mullerian duct syndrome