title: Alternative splicing and nonsense-mediated mRNA decay enforce neural specific gene expression.
abstract: Alternative pre-mRNA splicing is a fundamental regulatory process for most mammalian multi-exon genes to increase proteome diversity. Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance mechanism to mitigate deleterious effects caused by gene mutations or transcriptional errors. Coupling alternative splicing and NMD (AS-NMD), in which alternative splicing switches between translational and NMD isoforms, results in fine-tuning overall gene expression to, in turn, expand the functional activities of these two post-transcriptional regulatory processes. AS-NMD is known for maintaining homeostatic expression of many RNA-binding proteins. We further show that AS-NMD is a conserved mechanism among mammals to induce developmental expression of the synaptic scaffold protein PSD-95. Comparing gene sequences between human Psd-95 and its ancestral orthologues indicates that AS-NMD regulation of mammalian Psd-95 is a product of selective pressure and that it enforces neural-specific expression of PSD-95 proteins in mammals. Invertebrate homolog of Psd-95 is not subjected to AS-NMD regulation and its protein product does not exhibit neural-specific expression. Given the prevalence of alternative splicing regulation in the mammalian nervous system, neural-specific expression of many other genes could be controlled by AS-NMD in a similar manner. We discuss the implication of these discoveries, as well as the challenges in generalizing the regulation and functional activity of AS-NMD.
authors.affiliation: Division of Biomedical Sciences, University of California Riverside, University of California, 201 School of Medicine Research Building, 900 University Avenue, Riverside, CA 92521, United States. Electronic address: sika.zheng@ucr.edu.
authors.forename: Sika
authors.initials: S
authors.lastname: Zheng
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D015870:Gene Expression; D006801:Humans; D009474:Neurons / Q000502:physiology*; D059365:Nonsense Mediated mRNA Decay / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger