Functional compensation by Egr4 in Egr1-dependent luteinizing hormone regulation and Leydig cell steroidogenesis

The Egr family of zinc finger transcription factors, whose members are enco ded by Egr1 (NGFI-A), Egr2 (Krox20), Egr3, and Egr4 (NGFI-C) regulate criti cal genetic programs involved in cellular growth, differentiation, and func tion. Egr1 regulates luteinizing hormone beta subunit (LH beta) gene expres sion in the pituitary gland. Due to decreased levels of LH beta, female Egr 1-deficient mice are anovulatory, have low levels of progesterone, and are infertile, By contrast, male mutant mice show no identifiable defects in sp ermatogenesis, testosterone synthesis, or fertility. Here, we have shown th at 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 d ouble mutant male mice had low steady-state levels of serum LH, physiologic ally low serum levels of testosterone, and atrophy of androgen-dependent or gans that were not present in either Egr1- or Egr4-deficient males. In doub le mutant male mice, atrophic androgen-dependent organs and Leydig cell ste roidogenesis were fully restored by administration of exogenous testosteron e or human chorionic gonadotropin (an LH receptor agonist), respectively. M oreover, 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.