Nova-1 mediates glucocorticoid-induced inhibition of pre-mRNA splicing of gonadotropin-releasing hormone transcripts.
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.
Park
Eonyoung
E
School of Biological Sciences, Seoul National University, Seoul, Korea.
Lee
Mi Sun
MS
Baik
Sun Mi
SM
Cho
Eun Bee
EB
Son
Gi Hoon
GH
Seong
Jae Young
JY
Lee
Kun Ho
KH
Kim
Kyungjin
K
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
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