MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells

被引:110
作者
Greco, Steven J.
Rameshwar, Pranela [1 ]
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Div Hematol Oncol, Newark, NJ 07103 USA
[2] Univ Med & Dent New Jersey, Grad Sch Biomed Sci, Newark, NJ 07103 USA
关键词
neuron; Tac1; tachykinin; transdifferentiation; IL-1; alpha;
D O I
10.1073/pnas.0703037104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-1 alpha. 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-1 alpha 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 miR130a 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 ml in regulating neurotransmitter synthesis.
引用
收藏
页码:15484 / 15489
页数:6
相关论文
共 37 条
[1]   The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines [J].
Adams, Brian D. ;
Furneaux, Henry ;
White, Bruce A. .
MOLECULAR ENDOCRINOLOGY, 2007, 21 (05) :1132-1147
[2]   MIR-206 regulates connexin43 expression during skeletal muscle development [J].
Anderson, Curtis ;
Catoe, Heath ;
Werner, Rudolf .
NUCLEIC ACIDS RESEARCH, 2006, 34 (20) :5863-5871
[3]   Bone marrow stromal stem cells: Nature, biology, and potential applications [J].
Bianco, P ;
Riminucci, M ;
Gronthos, S ;
Robey, PG .
STEM CELLS, 2001, 19 (03) :180-192
[4]   MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development [J].
Boutz, Paul L. ;
Chawla, Geetanjali ;
Stoilov, Peter ;
Black, Douglas L. .
GENES & DEVELOPMENT, 2007, 21 (01) :71-84
[5]   Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers [J].
Calin, GA ;
Sevignani, C ;
Dan Dumitru, C ;
Hyslop, T ;
Noch, E ;
Yendamuri, S ;
Shimizu, M ;
Rattan, S ;
Bullrich, F ;
Negrini, M ;
Croce, CM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (09) :2999-3004
[6]   MicroRNA signatures in human cancers [J].
Calin, George A. ;
Croce, Carlo M. .
NATURE REVIEWS CANCER, 2006, 6 (11) :857-866
[7]   Neurons derived from human mesenchymal stem cells show synaptic transmission and can be induced to produce the neurotransmitter substance P by interleukin-1α [J].
Cho, KJ ;
Trzaska, KA ;
Greco, SJ ;
McArdle, J ;
Wang, FS ;
Ye, JH ;
Rameshwar, P .
STEM CELLS, 2005, 23 (03) :383-391
[8]   MicroRNA expression during chick embryo development [J].
Darnell, Diana K. ;
Kaur, Simran ;
Stanislaw, Stacey ;
Konieczka, Jay K. ;
Yatskievych, Tatiana A. ;
Antin, Parker B. .
DEVELOPMENTAL DYNAMICS, 2006, 235 (11) :3156-3165
[9]   Mesenchymal stem cells: Biology and potential clinical uses [J].
Deans, RJ ;
Moseley, AB .
EXPERIMENTAL HEMATOLOGY, 2000, 28 (08) :875-884
[10]   siRNAs can function as miRNAs [J].
Doench, JG ;
Petersen, CP ;
Sharp, PA .
GENES & DEVELOPMENT, 2003, 17 (04) :438-442