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 neuronal npcRNAs, 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). BC RNAs are effectors of RNA control at the synapse, and we posit that such control is a crucial determinant of 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.

Selected Publications

Muslimov, I. A., Banker, G., Brosius, J., and Tiedge, H. (1998). Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture. J. Cell Biol. 141, 1601-1611.

Tiedge, H., Bloom, F. E., and Richter, D. (1999). RNA, Whither Goest Thou? Science 283, 186-187.

Wang, H., Iacoangeli, A., Popp, S., Muslimov, I. A., Imataka, H., Sonenberg, N., Lomakin, I. B., and Tiedge, H. (2002). Dendritic BC1 RNA: functional role in regulation of translation initiation. J. Neurosci. 22, 10232-10241.

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.

Tiedge, H. (2005). RNA reigns in neurons. Neuron 48, 13-16.

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.

Lin, D., Pestova, T. V., Hellen, C. U., and Tiedge, H. (2008). Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol. Cell. Biol. 28, 3008-3019.

List of Publications (Pub Med)

Personnel

Emily Chen, M.D., Hematology/Oncology Fellow
Anna Iacoangeli, Ph.D., Research Assistant Professor
Daisy Lin, B.S., Graduate Student
Ilham A. Muslimov, M.D., Ph.D, Research Assistant Professor
David Paquiot, B.S., Student Volunteer
Arthur L. Rose, M.D., Professor of Pediatric Neurology
Jun Zhong, Ph.D., Research Assistant Professor

Service Functions

Reviewer for various scientific journals and funding organizations