Tourtellotte W G, Nagarajan R, Bartke A, Milbrandt J
Department of Pathology and Neuroscience Institute, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Mol Cell Biol. 2000 Jul;20(14):5261-8. doi: 10.1128/MCB.20.14.5261-5268.2000.
The Egr family of zinc finger transcription factors, whose members are encoded by Egr1 (NGFI-A), Egr2 (Krox20), Egr3, and Egr4 (NGFI-C) regulate critical genetic programs involved in cellular growth, differentiation, and function. Egr1 regulates luteinizing hormone beta subunit (LHbeta) gene expression in the pituitary gland. Due to decreased levels of LHbeta, female Egr1-deficient mice are anovulatory, have low levels of progesterone, and are infertile. By contrast, male mutant mice show no identifiable defects in spermatogenesis, testosterone synthesis, or fertility. Here, we have shown that serum LH levels in male Egr1-deficient mice are adequate for maintenance of Leydig cell steroidogenesis and fertility because of partial functional redundancy with the closely related transcription factor Egr4. Egr4-Egr1 double mutant male mice had low steady-state levels of serum LH, physiologically low serum levels of testosterone, and atrophy of androgen-dependent organs that were not present in either Egr1- or Egr4-deficient males. In double mutant male mice, atrophic androgen-dependent organs and Leydig cell steroidogenesis were fully restored by administration of exogenous testosterone or human chorionic gonadotropin (an LH receptor agonist), respectively. Moreover, a normal distribution of gonadotropin-releasing hormone-containing neurons and normal innervation of the median eminence in the hypothalamus, as well as decreased levels of LH gene expression in Egr4-Egr1-relative to Egr1-deficient male mice, indicates a defect of LH regulation in pituitary gonadotropes. These results elucidate a novel level of redundancy between Egr4 and Egr1 in regulating LH production in male mice.
锌指转录因子Egr家族的成员由Egr1（NGFI-A）、Egr2（Krox20）、Egr3和Egr4（NGFI-C）编码，它们调节参与细胞生长、分化和功能的关键基因程序。Egr1调节垂体中促黄体生成素β亚基（LHβ）的基因表达。由于LHβ水平降低，雌性Egr1缺陷小鼠无排卵，孕酮水平低，且不育。相比之下，雄性突变小鼠在精子发生、睾酮合成或生育能力方面未表现出明显缺陷。在此，我们发现雄性Egr1缺陷小鼠的血清LH水平足以维持睾丸间质细胞的类固醇生成和生育能力，这是因为与密切相关的转录因子Egr4存在部分功能冗余。Egr4-Egr1双突变雄性小鼠的血清LH稳态水平较低，睾酮的生理血清水平较低，且雄激素依赖器官萎缩，而这在Egr1或Egr4缺陷的雄性小鼠中均未出现。在双突变雄性小鼠中，分别通过给予外源性睾酮或人绒毛膜促性腺激素（一种LH受体激动剂），可使萎缩的雄激素依赖器官和睾丸间质细胞类固醇生成完全恢复。此外，含促性腺激素释放激素的神经元分布正常，下丘脑正中隆起的神经支配正常，且与Egr1缺陷雄性小鼠相比，Egr4-Egr1缺陷雄性小鼠中LH基因表达水平降低，这表明垂体促性腺细胞中LH调节存在缺陷。这些结果阐明了Egr4和Egr1在调节雄性小鼠LH产生方面新的冗余水平。
