The dynamic modulation of synaptic connections is a key underpinning of neuronal functionality and plasticity. In our lab, we work to understand how neurons orchestrate such modulations through local translational control of gene expression in synapto-dendritic domains.
The concept of local translational regulation at the synapse is attractive as it solves a central dilemma of long-term synaptic plasticity: the problem that long-lasting, activity-dependent alterations of synaptic strength on one hand 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, 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. But the functional components in the translation pathway that are targets of such control, and the molecular mechanisms that implement it, remain poorly understood. Uncontrolled translation is potentially deleterious as it may result in synaptic hyper-excitability. Translational regulation is therefore required at the synapse to control protein synthesis and to restrict it to times of demand (Tiedge, 2005, Neuron 48, 13-16). 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, Annu. Rev. Cell Dev. Biol. 21, 223-245).
Small BC RNAs, a subtype of regulatory RNAs in neurons, 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 RNA stem-loop domains (Muslimov et al., 2006, J. Cell Biol. 175, 427-439). BC1 and BC200 RNAs repress translation by targeting eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is required to unwind duplex elements in 5’ untranslated regions of mRNAs (Wang et al., 2005, J. Cell Biol. 171, 811-821; Lin et al., 2008, Mol. Cell. Biol. 28, 3008-3019).
Our recent work (Zhong et al., 2009, J. Neurosci.29, 9977-9986) has shown that BC1 regulation is required for the control of group I mGluR-stimulated synthesis of key synaptic proteins. Absence of BC1 RNA precipitates neuronal hyperexcitability that manifests in the form of prolonged epileptiform discharges, susceptibility to sound-induced seizures, and excessive synchronized cortical oscillations in the gamma frequency range. This hyperexcitability is dependent on protein synthesis, activation of group I mGluRs, and signaling through the MEK/ERK pathway.
In summary, BC RNAs are effectors of RNA control in neurons. Our research continues to be directed at the relevance of such control in neuronal functionality and plasticity.
Figure 1. RNA transport and local translation in neurons. Scenarios that may result from transsynaptic activity are indicated by yellow arrows in the dendritic spine (inset). (Illustration from Tiedge et al., 1999, Science 283, 186-187)
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, a mechanism that is indispensable for germ cell differentiation (Muslimov et al., 2002, J. Cell Sci. 115, 1243-1250).
(2) Dysregulated expression of such RNAs 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.
Eom, T., Berardi, V., Zhong, J., Risuleo, G., and Tiedge, H. (2011). Dual nature of translational control by regulatory BC RNAs. Mol. Cell. Biol. 31, 4538-4549.
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.
Taesun Eom, Ph.D., Research Assistant Professor
Anna Iacoangeli, Ph.D., Research Assistant Professor
Rabia Latif, M.D., Hematology/Oncology Physician Resident
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