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SPP1935 -- Deciphering the mRNP code :
RNA-bound Determinants of Post-transcriptional Gene Regulation

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laboratoriesProf. Dr. Sendtner

Michael Sendtner Center
University of Würzburg - Institute for Clinical Neurobiology

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Versbacherstr. 5 97078 Würzburg

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RNP functions in motoneurons, protein-RNA interactions

Colaboration with Dr. Michael Briese



Lab InfoPROJECT INFORMATION :

Motoneurons are highly polarized cells with long extensions termed axons along which electrical impulses are transmitted to the recipient cells. Particularly motoneurons in the spinal cord harbour axons that often bridge extensive distances in order to send electrical impulses to muscle cells. It is these “lower” motoneurons that are particularly affected in the neuromuscular disorder spinal muscular atrophy (SMA). In this disease a genetic defect causes lowered amounts of the Survival Motoneuron (SMN) protein and, in its most severe form, results in early childhood lethality due to motoneuron loss and muscle atrophy. In order to understand the mechanism underlying SMA more clearly it is important to investigate the cellular functions of the SMN protein as well as the cellular and molecular consequences of its loss from motoneurons. The central function of SMN is the production of spliceosomal snRNPs which are molecular particles involved in processing of messenger RNAs (mRNAs) that encode proteins. Considering that this process is crucial in all cells it is currently unclear how loss of SMN’s function in snRNP production could produce a specific loss of lower motoneurons that is characteristic for SMA. Therefore, we would like to investigate a novel function of SMN that has emerged over the last years. It has been shown that SMN as well as its interaction partner hnRNP R are present in axons of motoneurons. Since hnRNP R is an RNA-binding protein it is possible that messenger ribonucleoprotein particles (mRNPs) containing SMN, hnRNP R and other proteins as well as mRNAs are transported along axons in order to deliver the mRNAs to pre-synaptic structures for local protein production. To understand this process in further detail we would like to analyse the protein and mRNA composition of these SMN- and hnRNP R-mRNPs using proteome and RNA sequencing. As the next step we would analyse how the axonal delivery of these components is affected in mouse and cell culture models of SMA. Finally, we are planning to conduct experiments in which we perturb the axonal delivery of individual mRNAs contained within the SMN- and hnRNP R-mRNPs in order to pinpoint how the loss of selective mRNP components can affect neuronal function. Taken together, the results generated during the proposed project could shed light on the functions of mRNPs for axonal maintenance in general, and give further insights into the question how loss of SMN induces axonal dysfunction and, ultimately, motoneuron degeneration.



Lab techsKEY TECHNOLOGIES :

- Motoneuron culture
- Disease models
- iCLIP
- RNA pulldown
- In situ hybridization



PublicationsPUBLICATIONS :

Briese M, Saal L, Appenzeller S, Moradi M, Baluapuri A, Sendtner, M. Whole transcriptome profiling reveals the RNA content of motor axons. Nucleic Acids Res 44:e33 (2015)

Saal L, Briese M, Kneitz S, Glinka M, Sendtner M. Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation. RNA 20:1789-802 (2014)

Glinka M, Herrmann T, Funk N, Havlicek S, Rossoll W, Winkler C, Sendtner M. The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal ß-actin mRNA translocation in spinal motor neurons. Hum Mol Genet 19:1951-66 (2010)

Wiese S, Herrmann T, Drepper C, Jablonka S, Funk N, Klausmeyer A, Rogers ML, Rush R, Sendtner M. Isolation and enrichment of embryonic mouse motor neurons from the lumbar spinal cord of individual mouse embryos. Nat Protocols 5:31-38 (2010)

Rossoll W, Jablonka S, Andreassi C, Kröning AK, Karle K, Monani UR, Sendtner M. Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons. J Cell Biol 163:801-12 (2003)