Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development
2005
Mutations of orphan nuclear receptors SF1 and DAX1 each
cause adrenal insufficiency and gonadal dysgenesis in humans, although the
pathological features are distinct. Because Dax1 antagonizes Sf1-mediated
transcription in vitro, we hypothesized that Dax1 deficiency would
compensate for allelic loss of Sf1 . In studies of the developing
testis, expression of the fetal Leydig cell markers Cyp17 and
Cyp11a1 was reduced in heterozygous Sf1 -deficient mice at
E13.5, consistent with dose-dependent effects of Sf1 . In
Sf1/Dax1 ( Sf1 heterozygous and Dax1 -deleted) double
mutant gonads, the expression of these genes was unexpectedly reduced further,
indicating that loss of Dax1 did not compensate for reduced
Sf1 activity. The Sertoli cell product Dhh was reduced in
Sf1 heterozygotes at E11.5, and it was undetectable in
Sf1/Dax1 double mutants, indicating that Sf1 and
Dax1 function cooperatively to induce Dhh expression.
Similarly, Amh expression was reduced in both Sf1 and
Dax1 single mutants at E11.5, and it was not rescued by the
Sf1/Dax1 double mutant. By contrast, Sox9 was expressed in
single and in double mutants, suggesting that various Sertoli cell genes are
differentially sensitive to Sf1 and Dax1 function. Reduced
expression of Dhh and Amh was transient, and was largely
restored by E12.5. Similarly, there was recovery of fetal Leydig cell markers
by E14.5, indicating that loss of Sf1/Dax1 delays but does not
preclude fetal Leydig cell development. Thus, although Sf1 and Dax1 function
as transcriptional antagonists for many target genes in vitro, they act
independently or cooperatively in vivo during male gonadal development.
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