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

Warren G. Tourtellotte*, Rakesh Nagarajan, Andrzej Bartke, Jeffrey Milbrandt

*Corresponding author for this work

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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 (LHβ) gene expression in the pituitary gland. Due to decreased levels of LHβ, 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.

Original languageEnglish (US)
Pages (from-to)5261-5268
Number of pages8
JournalMolecular and cellular biology
Volume20
Issue number14
DOIs
StatePublished - Jul 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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