title: Regulatory roles of heterogeneous nuclear ribonucleoprotein M and Nova-1 protein in alternative splicing of dopamine D2 receptor pre-mRNA.
abstract: The dopamine D2 receptor (D2R) plays a crucial role in the regulation of diverse key physiological functions, including motor control, reward, learning, and memory. This receptor is present in vivo in two isoforms, D2L and D2S, generated from the same gene by alternative pre-mRNA splicing. Each isoform has a specific role in vivo, underlining the importance of a strict control of its synthesis, yet the molecular mechanism modulating alternative D2R pre-mRNA splicing has not been completely elucidated. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNP M) as a key molecule controlling D2R splicing. We show that binding of hnRNP M to exon 6 inhibited the inclusion of this exon in the mRNA. Importantly, the splicing factor Nova-1 counteracted hnRNP M effects on D2R pre-mRNA splicing. Indeed, mutations of the putative Nova-1-binding site on exon 6 disrupted Nova-1 RNA assembly and diminished the inhibitory effect of Nova-1 on hnRNP M-dependent exon 6 exclusion. These results identify Nova-1 and hnRNP M as D2R pre-mRNA-binding proteins and show their antagonistic role in the alternative splicing of D2R pre-mRNA.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Eonyoung
authors.initials: E
authors.lastname: Park
authors.forename: Ciro
authors.initials: C
authors.lastname: Iaccarino
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lee
authors.forename: Ilmin
authors.initials: I
authors.lastname: Kwon
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Baik
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.forename: Emiliana
authors.initials: E
authors.lastname: Borrelli
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D004285:Dogs; D005091:Exons / Q000502:physiology*; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000090682:Neuro-Oncological Ventral Antigen; D002679:Pan troglodytes; D011485:Protein Binding; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D034761:Heterogeneous-Nuclear Ribonucleoprotein Group M; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017448:Receptors, Dopamine D2