Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development
Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development
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DOI：
10.1242/dev.01826
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发表时间：
2005-05-01
期刊：
影响因子：
4.6
通讯作者：
Jameson, JL
中科院分区：
文献类型：
--
作者：
Park, SY;Meeks, JJ;Jameson, JL
孤儿核受体SF 1和DAX 1的突变分别导致人类肾上腺功能不全和性腺发育不全，尽管病理特征不同。由于Dax 1拮抗Sf 1介导的转录在体外，我们假设，Dax 1的缺陷将弥补等位基因损失的Sf 1。在睾丸发育的研究中，在E13.5时，杂合Sf 1缺陷小鼠中胎儿间质细胞标志物Cyp 17和Cyp 11 a1的表达降低，与Sf 1的剂量依赖性效应一致。在Sf 1/Dax 1（Sf 1杂合和Dax 1缺失）双突变性腺中，这些基因的表达意外地进一步降低，表明Dax 1的缺失并不能补偿Sf 1活性的降低。支持细胞产物Dhh在Sf 1杂合子E11.5中减少，在Sf 1/Dax 1双突变体中检测不到，表明Sf 1和Dax 1协同作用诱导Dhh表达。同样地，在E11.5，Sf 1和Dax 1单突变体中的Amh表达降低，并且Sf 1/Dax 1双突变体不能挽救Amh表达。相比之下，Sox 9在单突变体和双突变体中表达，表明各种支持细胞基因对Sf 1和Dax 1功能的敏感性不同。Dhh和Amh的表达减少是短暂的，并在E12.5时基本恢复。同样，在E14.5时胎儿间质细胞标志物恢复，表明Sf 1/Dax 1的丢失延迟但不妨碍胎儿间质细胞发育。因此，尽管Sf 1和Dax 1在体外作为许多靶基因的转录拮抗剂发挥作用，但它们在雄性性腺发育过程中在体内独立或协同作用。
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.