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Michael Sendtner Professor
Institut für Klinische Neurobiologie, Universität
Versbacherstr. 5, D-97078 Würzburg, Germany
Phone : 0931 201 44000
Fax : 0931 201 44009
E-Mail : Sendtner_M@ukw.de
Web : See online here
Non-coding RNAs are emerging as key regulators of cellular functions. Whilst the number of identified non-coding RNAs has increased substantially over the last years their individual role in specialized cells has remained relatively elusive. Highly polarized cells such as neurons might utilize non-coding RNAs to establish and maintain their often extensive axonal processes. Additionally, the role of non-coding RNAs in neurodegenerative diseases is not well-understood. In the proposed project we investigate the roles of the non-coding RNAs 7SK and Malat1 in spinal muscular atrophy (SMA), one of the most common genetic causes of infant lethality. In SMA, deficiency of the Survival Motor Neuron (SMN) protein causes degeneration of spinal motoneurons leading to atrophy of associated muscles. We previously identified the RNA-binding protein hnRNP R as an interactor of SMN. We characterized the RNA interactome of hnRNP R in motoneurons by iCLIP and found the non-coding RNA 7SK as the top candidate. We detected hnRNP R/7SK complexes in the cytosol of motoneurons including their axons and found that knockdown of either hnRNP R or 7SK reduced axon outgrowth accompanied by similar transcriptome alterations in the axons and somata. In the proposed project we would like to expand upon these findings and investigate the composition of cytosolic hnRNP R/7SK complexes by proteome analysis. We will then determine whether these complexes are altered in SMA motoneurons and to what extent deregulation of Malat1 as seen in SMA can cause alterations of such hnRNP R/7SK complexes. Taken together, the results generated in this project will help to further understand the functions of 7SK, Malat1 and hnRNP R in motoneurons and their roles in the pathomechanism of SMA.
Briese M, Saal-Bauernschubert L, Ji C, Moradi M, Ghanawi H, Uhl M, Appenzeller S, Backofen R, Sendtner M (2018) hnRNP R and its main interactor, the non-coding RNA 7SK, co-regulate the axonal transcriptome of motoneurons. PNAS 115:E2859-E2868
Moradi M, Sivadasan R, Saal L, Lüningschrör P, Dombert B, Rathod RJ, Dieterich DC, Blum R, Sendtner M (2017) Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons. J Cell Biol 216:793-814
Sivadasan R, Hornburg D, Drepper C, Frank N, Jablonka S, Hansel A, Lojewski X, Sterneckert J, Hermann A, Shaw PJ, Ince PG, Mann M, Meissner F, Sendtner M (2016) C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci 19:1610-1618
Briese M, Saal L, Appenzeller S, Moradi M, Baluapuri A, Sendtner M. 2015. Whole transcriptome profiling reveals the RNA content of motor axons. Nucl. Acids Res. doi: 10.1093/nar/gkv1027
Saal L, Briese M, Kneitz S, Glinka M, Sendtner M. 2014. Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation. RNA 20: 1789-1802.
Wagnon JL, Briese M, Sun W, Mahaffey CL, Curk T, Rot G, Ule J, Frankel WN. 2012. CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLoS Genet 8: e1003067.
Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V, et al. 2011. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14: 452-458.
Wiese S, Herrmann T, Drepper C, Jablonka S, Funk N, Klausmeyer A, Rogers ML, Rush R, Sendtner M. 2010. Isolation and enrichment of embryonic mouse motoneurons from the lumbar spinal cord of individual mouse embryos. Nat Protoc 5: 31-38.
Glinka M, Herrmann T, Funk N, Havlicek S, Rossoll W, Winkler C, Sendtner M. 2010. The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal beta-actin mRNA translocation in spinal motor neurons. Hum Mol Genet 19: 1951-1966.