Nova-1 Mediates Glucocorticoid-induced Inhibition of Pre-mRNA Splicing of Gonadotropin-releasing Hormone Transcripts

• Published in: The Journal of biological chemistry Vol. 284; no. 19; pp. 12792 - 12800
• Main Authors: Park, Eonyoung, Lee, Mi Sun, Baik, Sun Mi, Cho, Eun Bee, Son, Gi Hoon, Seong, Jae Young, Lee, Kun Ho, Kim, Kyungjin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Base Sequence; Blotting, Northern; Blotting, Western; Cross-Linking Reagents; Dexamethasone - pharmacology; Electrophoretic Mobility Shift Assay; Glucocorticoids - pharmacology; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; Introns; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; NIH 3T3 Cells; Reverse Transcriptase Polymerase Chain Reaction; RNA Precursors - genetics; RNA Splicing; RNA, Messenger - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Ultraviolet Rays
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M807386200

Glucocorticoid (GC) is known to affect the reproductive system by suppressing the gonadotropin-releasing hormone (GnRH) gene expression in the hypothalamus. However, the mechanism of this effect is poorly understood. We show here that the GC-induced reduction of GnRH mRNA is due to attenuation of a post-transcriptional process i.e. splicing of intron A. Treatment of dexamethasone (DEX), a synthetic GC, lowered GnRH mRNA transcripts and was accompanied by reduced excision of the first intron (intron A) from the GnRH pre-mRNA both in vitro and in vivo. While seeking to identify the splicing factors involved in GC-inhibited GnRH pre-mRNA splicing, we found that DEX down-regulated neuro-oncological ventral antigen-1 (Nova-1) mRNA and protein and that knockdown of Nova-1 reduced intron A excision from GnRH pre-mRNA. Nova-1 overexpression reversed the DEX-induced reduction of intron A excision. Nova-1 appears to promote intron A excision by binding to the distal region of exon 1 of the GnRH pre-mRNA. Taken together, our findings indicate that the intron A excision by Nova-1 is a target of GC for down-regulation of GnRH gene expression, and more importantly, we characterized Nova-1, a brain-enriched splicing regulator responsible for GnRH pre-mRNA splicing.