title: MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells.
abstract: MicroRNAs (miRNAs) are a class of 19- to 23-nt, small, noncoding RNAs, which bind the 3' UTR of target mRNAs to mediate translational repression in animals. miRNAs have been shown to regulate developmental processes, such as self-renewal of stem cells, neuronal differentiation, myogenesis, and cancer. A functional role of miRNAs in the regulation of neurotransmitter synthesis has yet to be ascribed. We used mesenchymal stem cells (MSCs) as a model to study miRNA-mediated neurotransmitter regulation in developing neuronal cells. MSCs are mesoderm-derived cells, primarily resident in adult bone marrow, which can generate functional neuronal cells. We have previously shown that human MSC-derived neuronal cells express the neurotransmitter gene, Tac1, but do not synthesize the gene's encoded peptide, the neurotransmitter substance P (SP), unless stimulated with the inflammatory mediator IL-1alpha. These findings suggested a potential role for miRNAs in the regulation of SP synthesis. Here, we report on the miRNA profile of undifferentiated human MSCs and MSC-derived neuronal cells by using miRNA-specific bioarrays. miRNAs that were increased in the neuronal cells and decreased after IL-1alpha stimulation were analyzed by the miRanda algorithm to predict Tac1 mRNA targets. Putative miR-130a, miR-206, and miR-302a binding sites were predicted within the 3' UTR of Tac1. Target validation using a luciferase reporter system confirmed the miR-130a and miR-206 sites. Specific inhibition of miR-130a and miR-206 in the neuronal cells resulted in SP synthesis and release. The studies provide a different approach in ascribing a new regulatory role for miRNAs in regulating neurotransmitter synthesis.
authors.affiliation: Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Greco
authors.forename: Pranela
authors.initials: P
authors.lastname: Rameshwar
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D002454:Cell Differentiation; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D015320:Tachykinins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D053582:Interleukin-1alpha; D035683:MicroRNAs; D018377:Neurotransmitter Agents; D015320:Tachykinins; D013373:Substance P