Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development

Dev Cell. 2013 Aug 26;26(4):416-30. doi: 10.1016/j.devcel.2013.06.018.


The Y-linked gene Sry regulates mammalian sex determination in bipotential embryonic gonads. Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation. Loss of Six1 and Six4 together, but neither alone, resulted in a male-to-female sex-reversal phenotype in XY mutant gonads accompanied by a failure in Sry activation. Decreased gonadal precursor cell formation at the onset of Sry expression and a gonadal size reduction in both sexes were also found in mutant embryos. Forced Sry transgene expression in XY mutant gonads rescued testicular development but not the initial disruption to precursor growth. Furthermore, we identified two downstream targets of Six1/Six4 in gonadal development, Fog2 (Zfpm2) and Nr5a1 (Ad4BP/Sf1). These two distinct Six1/Six4-regulated pathways are considered to be crucial for gonadal development. The regulation of Fog2 induces Sry expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Organ Size / genetics
  • Organogenesis
  • Sex Determination Processes / genetics*
  • Sex-Determining Region Y Protein / genetics
  • Sex-Determining Region Y Protein / metabolism
  • Spermatic Cord / embryology
  • Spermatic Cord / metabolism
  • Steroidogenic Factor 1 / genetics
  • Steroidogenic Factor 1 / metabolism
  • Testis / cytology
  • Testis / embryology*
  • Testis / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation / genetics


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Sex-Determining Region Y Protein
  • Six1 protein, mouse
  • Six4 protein, mouse
  • Steroidogenic Factor 1
  • Trans-Activators
  • Transcription Factors
  • Zfpm2 protein, mouse
  • steroidogenic factor 1, mouse