The Orphan Nuclear Receptor, Steroidogenic Factor 1, Regulates Neuronal Nitric Oxide Synthase Gene Expression in Pituitary Gonadotropes

Abstract

Steroidogenic factor 1 (SF-1), an essential nuclear receptor, plays key roles in steroidogenic cell function within the adrenal cortex and gonads. It also contributes to reproductive function at all three levels of the hypothalamic-pituitary-gonadal axis. SF-1 regulates genes in the steroidogenic pathway, such as LHbeta, FSHbeta, and steroid hydroxylase. Abundant evidence suggests that nitric oxide (NO) has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus and the preovulatory LH surge in pituitary gonadotropes. Recently, we cloned and characterized the promoter of mouse neuronal NO synthase (nNOS). nNOS is localized at all three levels of the hypothalamic-pituitary-gonadal axis to generate NO. We find that its major promoter resides at exon 2 in the pituitary gonadotrope alphaT3-1 cell line and that there is a nuclear hormone receptor binding site in this region, to which SF-1 can bind and regulate nNOS transcription. Mutation of the nuclear hormone receptor binding site dramatically decreases basal promoter activity and abolishes SF-1 responsiveness. A dominant negative of SF-1, in which the transactivation (AF-2) domain of SF-1 was deleted, inhibits nNOS exon 2 promoter activity. Dosage-sensitive reversal- adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1), which colocalizes and interferes with SF-1 actions in multiple cell lineages, negatively modulates SF-1 regulation of nNOS transcription. These findings demonstrate that mouse nNOS gene expression is regulated by the SF-1 gene family in pituitary gonadotropes. nNOS, a member of the cytochrome p450 gene family, could be one of the downstream effector genes, which mediates SF-1's reproductive function and developmental patterning.

Nuclear factor kappa-B mediates selective induction of neuronal nitric oxide synthase in astrocytes during low-level inflammatory stimulation with MPTP

“…Depolarization-induced Ca 2+ influx in cortical neurons through Ltype voltage-sensitive calcium channels is reported to induce Nos1 through a CREB responsive pathway at the second exon (Sasaki et al, 2000) and steroidogenic factor 1 (SF-1) is also reported to mediate inducible expression of mouse Nos1 (Wei et al, 2002). Involvement of NF-κB in regulation of mouse Nos1 is suggested by a separate report characterizing the organization of human Nos1 in which the presence of an NF-κB response element was documented in the promoter region flanking the first exon (Hall et al, 1994).…”

DNA Methylation in the Arginase–Nitric Oxide Synthase Pathway Is Associated with Exhaled Nitric Oxide in Children with Asthma

“…We examined CpG loci located in the promoter regions of NOS1, NOS2A, NOS3, ARG1, and ARG2 (see Figure E1 in the online supplement) (15,(18)(19)(20)(21)(22). For ARG1, a CpG locus in the promoter region (not in a CpG island), which was previously associated with change in expression, was selected (21).…”

“…Two CpG loci in a nuclear hormone receptor regulatory sequence in exon 2 of NOS1 were chosen for analysis, based on evidence that this nuclear hormone receptor site contributes to the regulation of NOS1 transcription (18). Three regions within the NOS2A gene were selected for DNA methylation analysis.…”

Gonadotropin-releasing hormone and the control of gonadotrope function

“…For both the GnRH receptor and the NOS I genes, evidence exists that the expression is up-regulated at proestrus of the ovarian cycle [31,44,45] suggesting a functional adaptation of the signalling machinery at this important physiological stage. GnRH receptor and NOS I promoters have been isolated and studies have characterised their tissue-specific and regulated expression in vitro using a transient transfection assay [36,[46][47][48][49][50][51] and/or in vivo using transgenesis [52][53][54]. In each case and regardless of their degree of characterisation, promoters appear to require a specific combination of transcription factors to achieve both tissue-specific and regulated gene expression as illustrated for the GnRH receptor gene in Figure 1.…”