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 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.
Tourtellotte
W G
WG
Department of Pathology and Neuroscience Institute, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Nagarajan
R
R
Bartke
A
A
Milbrandt
J
J
D000818:Animals; D000858:Anovulation / Q000235:genetics; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006720:Homozygote; D007031:Hypothalamus / Q000378:metabolism; D017874:Immediate-Early Proteins; D007247:Infertility, Female / Q000235:genetics; D007985:Leydig Cells / Q000502:physiology*; D007986:Luteinizing Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D010902:Pituitary Gland / Q000378:metabolism; D011467:Prostate / Q000002:abnormalities / Q000187:drug effects; D013091:Spermatogenesis / Q000235:genetics; D013256:Steroids / Q000378:metabolism*; D013737:Testis / Q000502:physiology; D013739:Testosterone / Q000097:blood / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; C486109:Egr1 protein, mouse; C486392:Egr4 protein, mouse; D037201:Follicle Stimulating Hormone, beta Subunit; D017874:Immediate-Early Proteins; D013256:Steroids; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone