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Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis
Susan Y Park1, Joshua J Meeks, Gerald Raverot
1Division of Endocrinology and Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Development (Cambridge, England)
|April 15, 2005
Summary
Loss of Dax1 does not compensate for reduced Steroidogenic Factor 1 (SF1) activity in developing testes. Instead, SF1 and Dax1 cooperate to regulate Sertoli cell gene expression, with their combined absence delaying but not preventing Leydig cell development.
Area of Science:
- Endocrinology
- Developmental Biology
- Genetics
Background:
- Mutations in orphan nuclear receptors SF1 and DAX1 cause adrenal and gonadal disorders.
- DAX1 is known to antagonize SF1-mediated transcription in vitro.
- This antagonism suggests DAX1 deficiency might compensate for reduced SF1 activity.
Purpose of the Study:
- To investigate the in vivo roles of SF1 and DAX1 in male gonad development.
- To determine if DAX1 deficiency can compensate for reduced SF1 activity in the developing testis.
- To elucidate the cooperative or independent functions of SF1 and DAX1 in regulating gonadal gene expression.
Main Methods:
- Analysis of gene expression in wild-type, Sf1-heterozygous, Dax1-deleted, and double mutant mouse embryonic gonads.
- Quantitative assessment of fetal Leydig cell markers (Cyp17, Cyp11a1) and Sertoli cell markers (Dhh, Amh, Sox9) at various embryonic stages (E11.5-E14.5).
Main Results:
- Reduced expression of fetal Leydig cell markers in Sf1 heterozygotes was further decreased in Sf1/Dax1 double mutants, refuting compensation.
- Sertoli cell markers Dhh and Amh showed reduced or undetectable expression in double mutants, indicating cooperative function.
- Sox9 expression was maintained in single and double mutants, suggesting differential gene sensitivity.
- Gene expression deficits were largely transient, with recovery observed by E12.5-E14.5, indicating delayed rather than blocked development.
Conclusions:
- DAX1 loss does not compensate for reduced SF1 activity in vivo.
- SF1 and DAX1 function cooperatively to regulate key genes like Dhh and Amh during male gonad development.
- Despite in vitro antagonism, SF1 and DAX1 exhibit independent or cooperative roles in vivo, influencing gonadal development timing.