Research Group Mohr
Control of protein synthesis in nerve cells
Neurons are considered the most complex cell type of all higher organisms. The constituents of the nervous system are interconnected via thousands of synaptic contacts, thus forming an elaborate communication network. Synapses are constantly remodelled, subsequent to synaptic input, and memory formation and storage in neuronal networks depends on new protein synthesis, which can occur locally at synapses using the translational machinery present in dendrites and on spines. These new proteins support long-lasting changes in synapse strength and size in response to high levels of synaptic activity. To ensure that proteins are made at the appropriate time and location to enable these synaptic changes, both messenger RNA (mRNA) transport and translation are tightly controlled by RNA-binding proteins (schematically depicted in Figure 1).
Translation encompasses three steps: initiation, elongation and termination. Initiation commences with the binding of eukaryotic initiation factor (eIF) 4F at the 5'-end of the mRNA molecule. eIF4F is a ternary complex consisting of the cap-binding protein eIF4E, the scaffolding protein eIF4G and the RNA helicase eIF4A. These protein/protein interactions are stabilized by the poly(A) tail-associated poly(A)-binding protein (PABP) giving rise to the formation of a closed loop between the 5'- and 3'-ends of the transcript. Subsequently, the small ribosomal subunit with its associated factors (43S preinitiation complex) is recruited, resulting in the 48S initiation complex. After scanning the mRNA towards the 3'-end to find the (mostly) first AUG codon, eIFs leave the complex, thus clearing the way for the large 60S ribosomal subunit to join. With the formation of the 80S complex, initiation is completed and elongation can commence.
Central to this project is the still largely unresolved question of how translation of localized mRNA species is activated as a consequence of synaptic stimulation. We have characterized a protein, makorin RING zinc-finger protein-1 (MKRN1), in rodent neurons that likely plays a role in translation of dendritic mRNAs. MKRN1, a bona fide RNA-binding protein, is a novel PABP-interacting protein, a potent stimulator of protein synthesis initiation, and it is associated with dendritically localized mRNAs. Furthermore, high-frequency stimulation of the rat entorhinal cortex in vivo, which produces robust long-term potentiation (LTP), leads to a specific accumulation of MKRN1 at activated synapses in the middle molecular layer of the hippocampal dentate gyrus. This paradigm induces local translation of dendritic mRNAs in the very same region. The data indicate that MKRN1 interacts with PABP, and presumably additional proteins, to control translation of mRNAs localized to neuronal dendrites. Current research aims at identifying and characterizing the MKRN1 interactome, in order to gain a deeper understanding of how protein synthesis in neuronal processes is regulated subsequent to synaptic activation.
Figure 1: Model of mRNA transport and local translation in dendrites of nerve cells. Transport of distinct mRNA species to neurites of nerve cells commences in the cell nucleus where the nucleic acids associate with RNA-binding protein(s) to give rise to ribonucleoprotein complexes. In the cytosol these complexes are likely remodeled and recruited to microtubules along which they are targeted to their final destination within dendrites. During transport translation is blocked by RNA-binding proteins. Eventually, translational silencing is overcome and localized mRNAs are translated at activated synapses.
- André Friedrich
- Björn Meyer-Hiemer
- Hatmone Miroci
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- Mohr, E., Fuhrmann, C. & Richter, D. (2001). VP-RBP, a protein enriched in brain tissue specifically interacts with the dendritic localizer sequence of the rat vasopressin mRNA. Eur. J. Neurosci. 13, 1107-1112.
- Mohr, E. & Richter, D. (2001). Messenger RNA on the move: implications for cell polarity. Int. J. Biochem. Cell Biol. 33, 669-679.
- Mohr, E., Prakash, N., Vieluf, K., Fuhrmann, C., Buck, F. & Richter, D. (2001). Vasopressin mRNA localization in nerve cells: characterization of cis-acting elements and trans-acting factors. Proc. Natl. Acad. Sci. USA 98, 7072-7079.
- Mohr, E., Kächele, I., Mullin, C. & Richter, D. (2002) Rat vasopressin mRNA: a model system to characterize cis-acting elements and trans-acting factors involved in dendritic mRNA sorting. Prog. Brain Res. 139, 211-224.
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- Mohr E. and Richter, D. (2003) Molecular determinants and physiological relevance of extrasomatic RNA localization in neurons. Front. Neuroendocrinol. 24, 128-139.
- Mohr, E. and Richter, D. (2004) Subcellular VP mRNA trafficking and local translation in dendrites. J. Neuroendocrinol. 16, 333-339.
- Mullin, C., Duning, K., Barnekow, A., Richter, D., Kremerskothen, J. and Mohr, E. (2004) Interaction of rat poly(A)-binding protein with poly(A)- and non-poly(A) sequences is preferentially mediated by RNA recognition motifs 3+4. FEBS Lett. 556, 437-441.
- Napoli,I., Mercaldo,V., Pilo Boyl, P., Eleuteri, B., Zalfa, F., De Rubeis,S., Di Marino, D., Mohr, E., Massimi,M., Falconi, M., Witke, W., Costa-Mattioli, M., Sonenberg, N., Achsel, T., Bagni, C. (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054.
- Miroci, H., Schob, C., Kindler, S., Ölschläger-Schütt, J., Fehr, S., Jungenitz, T., Schwarzacher, S. W., Bagni, C., Mohr, E. (2012) Makorin ring zinc-finger protein 1 (MKRN1), a novel poly(A)-binding protein-interacting protein, stimulates translation in nerve cells. J. Biol. Chem. 287, 1322-1334.