The dynamic modulation of synaptic connections is a key underpinning of neuronal functionality and plasticity. In our lab, we work to understand how neurons implement such modulation through local translational control of gene expression in synapto-dendritic domains.
The concept of local translational regulation at the synapse addresses a central conundrum of long-term synaptic plasticity: the problem that long-lasting, activity-dependent alterations of synaptic strength depend on changes of gene expression but on the other hand require that such changes be instituted in an input-responsive, locally restricted manner. With local control of gene expression, a synapse acquires independent decision-making authority, an essential prerequisite for the differential modulation of thousands of input-receptive postsynaptic domains.
Local translation at the synapse is modulated by physiological stimuli such as transsynaptic activity and trophic action. Our work is directed at molecular mechanisms that couple the action of such stimuli to the control of local translation. Such control is essential to restrict synaptic protein synthesis to times of demand. Several types of translational regulators have been identified at postsynaptic sites, prominent among them small BC RNAs and the fragile X mental retardation protein (FMRP) (Kindler et al., 2005; Iacoangeli and Tiedge, 2013).
Neuronal BC RNAs are translational repressors that are highly abundant in dendrites and at the synapse. They are targeted to postsynaptic domains by virtue of spatial codes that are contained in noncanonical RNA motif structures (Muslimov et al., 2006, 2011). BC1 and BC200 RNAs reversibly repress translation by targeting eukaryotic initiation factors 4A and 4B (Wang et al., 2005; Eom et al., 2014). BC RNA translational control rapidly shifts from a repressive to a permissive state upon receptor activation, a switch that is brought about by dephosphorylation of eIF4B, release of BC RNA from the factor, and initiation of translation (Eom et al., 2014).
Research with model animals (Zhong et al., 2009) has shown that absence of BC1 RNA precipitates neuronal hyperexcitability that manifests in the form of prolonged epileptiform discharges and susceptibility to convulsive seizures. Dysregulated neuronal RNA control can thus be a cause of neurological impairment.
Figure 1. RNA transport and local translation in neurons. BC RNAs control translation of local mRNAs at the synapse. Components not drawn to scale. For details, see Iacoangeli and Tiedge, 2013.
Research in Tumor Biology
We are conducting an independent research project that is aimed at establishing the biological relevance of BC RNAs in tumor cells, and at developing early cancer diagnostic and prognostic tools. Based on our finding that BC RNAs are detectable at significant levels in oocytes and spermatogonia as well as in various types of malignant tumor cells, we suggest that:
(1) BC RNAs play a key role in translational control in germ cells (Muslimov et al., 2002, J. Cell Sci. 115, 1243-1250).
(2) Dysregulated BC200 RNA expression results in altered translational control in malignant tumor cells.
Our research is aimed at establishing the role of BC RNAs in translational control mechanisms in tumor cells, its functional relevance in tumorigenesis and tumor progression, and the clinical utility of dysregulated expression in tumor cells. In particular, we will develop the utility of BC200 expression for tumor diagnosis and prognosis (Iacoangeli et al., 2004, Carcinogenesis 25, 2125-2133). This work is covered by several awarded and pending patents.
Kindler, S., Wang, H., Richter, D., and Tiedge, H. (2005). RNA transport and local control of translation. Annu. Rev. Cell Dev. Biol. 21, 223-245.
Wang, H., Iacoangeli, A., Lin, D., Williams, K., Denman, R. B., Hellen, C. U. T., and Tiedge, H. (2005). Dendritic BC1 RNA in translational control mechanisms. J. Cell Biol. 171, 811-821.
Muslimov, I. A., Iacoangeli, A., Brosius, J., and Tiedge, H. (2006). Spatial codes in dendritic BC1 RNA. J. Cell Biol. 175, 427-439.
Mus, E., Hof, P. R., and Tiedge, H. (2007). Dendritic BC200 RNA in aging and in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 104, 10679-10684.
Iacoangeli, A., Rozhdestvensky, T. S., Dolzhanskaya, N., Tournier, B., Schütt, J., Brosius, J., Denman, R. B., Khandjian, E. W., Kindler, S., and Tiedge, H. (2008). On BC1 RNA and the fragile X mental retardation protein. Proc. Natl. Acad. Sci. USA 105, 734-739.
Zhong, J., Chuang, S. C., Bianchi, R., Zhao, W., Lee, H., Fenton, A. A., Wong, R. K., and Tiedge, H. (2009). BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability. J. Neurosci. 29, 9977-9986. Editorial Comment J. Neurosci. 29 page i.
Muslimov, I. A., Patel, M. V., Rose, A., and Tiedge, H. (2011). Spatial code recognition in neuronal RNA targeting: Role of RNA – hnRNP A2 interactions. J. Cell Biol. 194, 441-457. Highlighted in JCB Editorial Short, B. (2011). RNA targeting gets competitive. J. Cell Biol. 194, 350.
Iacoangeli, A., and Tiedge, H. (2013). Translational control at the synapse: role of RNA regulators. Trends Biochem. Sci. 38, 47-55.
Muslimov, I .A., Tuzhilin, A., Tang, T. H., Wong, R. K. S., Bianchi, R., and Tiedge, H. (2014). Interactions of noncanonical motifs with hnRNP A2 promote activity-dependent RNA transport in neurons. J. Cell Biol. 205, 493-510. Featured in Biobytes Podcast.
Eom, T., Muslimov, I. A., Tsokas, P., Berardi, V., Zhong, J., Sacktor, T. C., and Tiedge, H. (2014). Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. J. Cell Biol. 207:237-252.
Taesun Eom, Ph.D., Research Assistant Professor
Kumar Guddati, M.D., Ph.D., Hematology/Oncology Fellow
Anna Iacoangeli, Ph.D., Research Assistant Professor
Elzbieta Mechel, B.S., Medical Student
Ilham A. Muslimov, M.D., Ph.D, Research Scientist
Arthur L. Rose, M.D., Professor of Pediatric Neurology
Reviewer for various scientific journals and funding organizations