Fox tales: regulation of gonadotropin gene expression by forkhead transcription factors

Abstract

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced by pituitary gonadotrope cells and are required for steroidogenesis, the maturation of ovarian follicles, ovulation, and spermatogenesis. Synthesis of LH and FSH is tightly regulated by a complex network of signaling pathways activated by hormones including gonadotropin-releasing hormone, activin and sex steroids. Members of the forkhead box (FOX) transcription factor family have been shown to act as important regulators of development, homeostasis and reproduction. In this review, we focus on the role of four specific FOX factors (FOXD1, FOXL2, FOXO1 and FOXP3) in gonadotropin hormone production and discuss our current understanding of the molecular function of these factors derived from studies in mouse genetic and cell culture models.

Keywords: Follicle-stimulating hormone; Forkhead; Gonadotrope; Luteinizing hormone; Pituitary; Transcription.

Figure 1

Structural organization of the FOXD1, FOXL2, FOXO1, and FOXP3 proteins. Numbering of the amino acids is relevant to the human proteins. Abbreviations: DBD, DNA-binding domain; Poly A, polyalanine tract; NLS, nuclear localization signal; NES, nuclear export signal; TAD, transactivation domain; Pro Rich, proline rich domain; Leu, leucine.

Figure 2

Schematic of SMAD and FOXL2 binding elements on the FSHB promoter. SBE, Smad-binding element; m, murine; p, porcine; h, human. SBEs are underlined and FOXL2 binding elements are in bold.

Figure 3

FOXO1 is expressed in adult murine gonadotropes and thyrotropes while FOXO3 is expressed in thyrotropes and corticotropes. Adult murine pituitary tissue sections were processed and imaged at 40× magnification, as described previously (Arriola et al., 2012). Dual-fluorescence labeling was performed on the same section with A) rabbit anti-human FOXO1 (H-128; Santa Cruz Biotechnology; 1:100 dilution in 10% goat serum/0.3% Triton X-100) or B) anti-human FOXO3 (75D8; Cell Signaling Technology, Inc.; 1:200) and either guinea pig anti-rat LHB (1:200), TSHB (1:200), GH (1:200), PRL (1:10,000), or ACTH (1:10,000) primary antibodies from the NIDDK National Hormone and Pituitary Program for 48 h at 4°C. The sections were then incubated with goat anti-rabbit and anti-guinea pig Alexa Fluor 488 and 594 (Invitrogen; 1:400) secondary antibodies for 1 h at room temperature. Red arrows indicate LHB, TSHB, GH, PRL or ACTH. Green arrows indicate FOXO1 (A) or FOXO3 (B). Yellow arrows indicate FOXO colocalization with proteins representing the five endocrine cell types in the anterior pituitary. Yellow signal in FOXO3-GH image is due to auto fluorescence of erythrocytes.