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First published online 13 April 2005
doi: 10.1242/dev.01826

Development 132, 2415-2423 (2005)
Published by The Company of Biologists 2005
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Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development

Susan Y. Park1, Joshua J. Meeks1, Gerald Raverot1, Liza E. Pfaff1, Jeffrey Weiss1, Gary D. Hammer2 and J. Larry Jameson1,*

1 Division of Endocrinology and Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2 Division of Endocrinology and Medicine and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA

* Author for correspondence (e-mail: ljameson{at}northwestern.edu)

Accepted 16 March 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.

Key words: Sf1, Dax1, Gonad, Mouse embryo, Nuclear receptor




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