Department of Physiology, Southern Illinois University, Carbondale, Carbondale, Illinois 62901-6523, USA.
Biol Reprod. 2012 May 10;86(5):144, 1-9. doi: 10.1095/biolreprod.111.094904. Print 2012 May.
The hypothalamic-pituitary-gonadal axis is central to normal reproductive function. This pathway begins with the release of gonadotropin-releasing hormone in systematic pulses by the hypothalamus. Gonadotropin-releasing hormone is bound by receptors on gonadotroph cells in the anterior pituitary gland and stimulates the synthesis and secretion of luteinizing hormone and, to some extent, follicle-stimulating hormone. Once stimulated by these glycoprotein hormones, the gonads begin gametogenesis and the synthesis of sex hormones. In humans, mutations of the forkhead transcription factor, FOXP3, lead to an autoimmune disorder known as immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. Mice with a mutation in the Foxp3 gene have a similar autoimmune syndrome and are infertile. To understand why FOXP3 is required for reproductive function, we are investigating the reproductive phenotype of Foxp3 mutant mice (Foxp3(sf/Y)). Although the gonadotroph cells appear to be intact in Foxp3(sf/Y) mice, luteinizing hormone beta (Lhb) and follicle-stimulating hormone beta (Fshb) expression are significantly decreased, demonstrating that these mice exhibit a hypogonadotropic hypogonadism. Hypothalamic expression of gonadotropin-releasing hormone is not significantly decreased in Foxp3(sf/Y) males. Treatment of Foxp3(sf/Y) males with a gonadotropin-releasing hormone receptor agonist does not rescue expression of Lhb or Fshb. Interestingly, we do not detect Foxp3 expression in the pituitary or hypothalamus, suggesting that the infertility seen in Foxp3(sf/Y) males is a secondary effect, possibly due to loss of FOXP3 in immune cells. Pituitary expression of glycoprotein hormone alpha (Cga) and prolactin (Prl) are significantly reduced in Foxp3(sf/Y) males, whereas the precursor for adrenocorticotropic hormone, pro-opiomelanocortin (Pomc), is increased. Human patients diagnosed with IPEX often exhibit thyroiditis due to destruction of the thyroid gland by autoimmune cells. We find that Foxp3(sf/Y) mice have elevated expression of thyroid-stimulating hormone beta (Tshb), suggesting that they may suffer from thyroiditis as well. Expression of the pituitary transcription factors, Pitx1, Pitx2, Lhx3, and Egr1, is normal; however, expression of Foxl2 and Gata2 is elevated. These data are the first to demonstrate a defect at the pituitary level in the absence of FOXP3, which contributes to the infertility observed in mice with Foxp3 loss of function mutations.
下丘脑-垂体-性腺轴是正常生殖功能的核心。这条途径始于下丘脑系统脉冲释放促性腺激素释放激素。促性腺激素释放激素与垂体前叶中的促性腺细胞上的受体结合，并刺激黄体生成素和在一定程度上促卵泡激素的合成和分泌。一旦被这些糖蛋白激素刺激，性腺开始进行配子发生和性激素的合成。在人类中，叉头框转录因子 FOXP3 的突变导致一种自身免疫性疾病，称为免疫调节、多内分泌腺病和肠病、X 连锁综合征。Foxp3 基因突变的小鼠具有类似的自身免疫综合征并且不育。为了了解为什么 FOXP3 是生殖功能所必需的，我们正在研究 Foxp3 突变小鼠（Foxp3(sf/Y)）的生殖表型。尽管 Foxp3(sf/Y) 小鼠中的促性腺细胞似乎完整，但黄体生成素β（Lhb）和促卵泡激素β（Fshb）的表达显著降低，表明这些小鼠表现出促性腺激素缺乏性性腺功能减退症。Foxp3(sf/Y) 雄性的下丘脑促性腺激素释放激素表达没有显著降低。用促性腺激素释放激素受体激动剂治疗 Foxp3(sf/Y) 雄性不能挽救 Lhb 或 Fshb 的表达。有趣的是，我们在垂体或下丘脑均未检测到 Foxp3 的表达，这表明 Foxp3(sf/Y) 雄性的不育是继发效应，可能是由于免疫细胞中 FOXP3 的缺失所致。Foxp3(sf/Y) 雄性的垂体糖蛋白激素α（Cga）和催乳素（Prl）的表达显著降低，而促肾上腺皮质激素的前体，前阿黑皮素原（Pomc）增加。被诊断患有 IPEX 的人类患者由于自身免疫细胞破坏甲状腺而经常患有甲状腺炎。我们发现 Foxp3(sf/Y) 小鼠的促甲状腺激素β（Tshb）表达升高，这表明它们也可能患有甲状腺炎。垂体转录因子 Pitx1、Pitx2、Lhx3 和 Egr1 的表达正常；然而，Foxl2 和 Gata2 的表达升高。这些数据首次证明了在没有 FOXP3 的情况下，垂体水平存在缺陷，这导致了 Foxp3 功能丧失突变小鼠的不育。
