title: Nova-1 mediates glucocorticoid-induced inhibition of pre-mRNA splicing of gonadotropin-releasing hormone transcripts.
abstract: 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.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Eonyoung
authors.initials: E
authors.lastname: Park
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Lee
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Baik
authors.forename: Eun Bee
authors.initials: EB
authors.lastname: Cho
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.forename: Kun Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D003432:Cross-Linking Reagents; D003907:Dexamethasone / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D005938:Glucocorticoids / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000090682:Neuro-Oncological Ventral Antigen; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays
chemical_list: D000951:Antigens, Neoplasm; D003432:Cross-Linking Reagents; D005938:Glucocorticoids; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D007987:Gonadotropin-Releasing Hormone; D003907:Dexamethasone