Maurice Swanson, M.S., Ph.D.
Associate Director of CNG
Professor of UF MGM
Phone: (352) 273-8076
Fax: (352) 273-8284
University of Florida
Dept. of Molecular Genetics & Microbiology
2033 Mowry Road
Gainesville, FL. 32610
My early studies on RNA binding proteins involved in RNA processing, including members of the hnRNP family, led to the discovery of several protein motifs (e.g., RRM), which showed sequence-dependent interactions with target RNA sequences. This observation led to an interest in microsatellites since they are tandem repeats. Following the discovery of microsatellite expansion mutations as the cause of a number of neurological diseases, including fragile X (FRAXA) and myotonic dystrophy (DM), I became interested in the molecular basis of DM because the expansion mutation is located in the 3’ untranslated region (3’ UTR) of the DMPK gene and yet the inheritance pattern is autosomal dominant. We proposed the RNA-mediated pathogenesis model for DM whereby disease-associated mutations are transcribed into expansion RNAs that are pathogenic because they sequester cellular factors required for normal cell functions. To provide evidence for this model, we identified and characterized the first CUG-binding protein, CUGBP1/CELF1, but subsequent studies failed to confirm that CELF1 was a sequestered factor. This led us to develop a repeat-dependent crosslinking assay that resulted in the discovery of the muscleblind-like (MBNL) protein family and subsequent confirmation that MBNL loss-of-function is a major pathogenic event in DM. another major effort of our research group has been to understand how proteins interact with RNA structures and how these interactions lead to the formation of nuclear RNA foci. Additionally, we have clarified the functional differences between MBNL family members (MBNL1, MBNL2 and MBNL3) in RNA processing in different tissues and these studies have resulted in the current model that DM is a MBNL compound loss-of-function disease. Our analysis has provided an experimental basis to examine the roles of other microsatellite expansions in neurological disease, including C9orf72 ALS/FTD
Research in the Swanson lab
Dr. Swanson’s research has focused on the fundamental mechanisms involved in pre-mRNA processing, including splicing and polyadenylation. A major objective has been to address the question of how RNA processing is regulated during embryonic, fetal and postnatal development and how this regulation is disrupted in neurological disease, particularly in microsatellite expansion disorders. Our primary experimental system is the mouse and we have generated a number of knockout, knockin and transgenic lines to investigate the roles of specific RNA-binding proteins in disease pathogenesis. As the PI or Co-PI on a number of NIH-funded grants, Dr. Swanson has been responsible for administering these projects and also developing collaborations with a wide range of investigators to generate results that have had a significant impact on our understanding of RNA processing in mammalian development and disease. More specific details are research in the Swanson lab are given below.
Dynamic Mutations, Non-Coding RNAs and RNA-Mediated Disease
The human genome contains a complex array of repetitive DNA sequence elements including transposon-derived/interspersed repeats, segmental duplications, large tandemly repeated sequences and simple sequence repeats (microsatellites). Microsatellite instability is associated with nearly 30 hereditary disorders. Disease may result from repeat expansions within a coding region and synthesis of a toxic protein (e.g., Huntington’s disease). Alternatively, many microsatellites are located in non-coding regions and cause diseases such as spinocerebellar ataxia types 8, 10 and 12 (SCA8, SCA10, SCA12), fragile X-associated tremor ataxia syndrome (FXTAS) and several types of myotonic dystrophy (CDM, DM1, DM2). How do simple repeat expansions in non-coding regions result in disease? To answer this question, we have focused on myotonic dystrophy because it is a dominantly-inherited disorder associated with non-coding CTG and CCTG expansion mutations in two different genes, DMPK (DM1) and ZNF9 (DM2), which lead to similar disease phenotypes. We proposed the RNA-mediated disease model in which mutant DM1 and DM2 mRNAs are trapped in the nucleus and sequester (C)CUG repeat binding proteins that are essential for normal tissue development and maintenance. Our lab identified these sequestered factors as the muscleblind-like (MBNL) proteins. Ongoing efforts are focused on elucidating the normal functions of these proteins as well as investigating whether RNA toxicity has a pathogenic role in other hereditary disorders.
Regulation of RNA Processing During Development
During embryogenesis and postnatal development, mammalian tissues are initially formed and subsequently remodeled to meet the evolving demands of the developing organism. This process requires a dynamic series of biochemical events at both the transcriptional and post-transcriptional levels. While considerable effort has been spent on clarifying DNA sequence elements and trans-acting factors involved in transcriptional regulation, less is known about the post-transcriptional steps required for normal tissue genesis and maturation. Many genes encode multiple protein isoforms that are generated by alterative splicing of pre-mRNAs and we are interested in understanding the mechanistic basis for these splicing transitions during skeletal muscle and brain development. Recent studies have focused on the roles of two alternative splicing factors, MBNL1 and CUGBP1, in regulating alternative exon splicing during the neonatal to adult transition. We are currently investigating additional factors and pathways that impact RNA processing during development and how disruption of these pathways results in disease.
Neurodegeneration in Myotonic Dystrophy
The human brain contains ~1011 neurons which are interconnected through a vast network of synapses. This highly interactive cell system requires an extraordinary level of protein diversity, much of which is generated by alternative processing of gene transcripts. The brain is severely affected by the multi-systemic disorder myotonic dystrophy (DM). These CNS effects can be subdivided into developmental (DM type 1 disease only) and degenerative changes (DM1 and DM2). This distinction between DM1 and DM2 in the CNS is strikingly similar to disease-associated effects observed in muscle where developmental abnormalities (e.g., hypotonia, respiratory insufficiency) are only observed in DM1 (congenital DM1 or CDM) while adult-onset degenerative changes (muscle weakness/wasting) occur in both DM1 and DM2. Our long term goal is to test the hypothesis that DM-associated CNS deficits result from disruption of the normal steps in the expression and pre-mRNA processing of specific gene transcripts and to clarify how the corresponding biochemical pathways are adversely affected in the DM brain.
Freyermuth, F., Rau, F., Kokunai, Y., Linke, T., Sellier, C., Nakamori, M., Kino, Y., Arandel, L., Jollet, A., Thibault, C., Philipps, M., Vicaire, S., Jost, B., Udd, B., Day, J.W., Duboc, D., Wahbi, K., Matsumura, T., Fujimura, H., Mochizuki, H., Deryckere, F., Kimura, T., Nukina, N., Ishiura, S., Lacroix, V., Campan-Fournier, A., Navratil, V., Chautard, E., Auboeuf, D., Horie, M., Imoto, K., Lee, K.Y., Swanson, M.S., Lopez de Munain, A., Inada, S., Itoh, H., Nakazawa, K., Ashihara, T., Wang, E., Zimmer, T., Furling, D., Takahashi, M.P., N. Charlet-Berguerand. (2016). Splicing mis-regulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Commun., 7:11067. doi: 10.1038/ncomms11067.
Taliaferro, J.M., Vidaki, M., Oliveira, R., Olson, S., Zhan, L., Saxena, T., Wang, E.T., Graveley, B.R., Gertler, F.B., Swanson, M.S., and C.B. Burge. (2016). Distal alternative last exons localize mRNAs to neural projections. Cell 61:821-833.
Scotti, M., and M.S. Swanson. (2016). RNA mis-splicing in disease. Nat Rev. Genet. 17:19-32.
Davis, J., Salomonis, N., Ghearing, N., Lin, S-C. J., Kwong, J.Q., Mohan, A., Swanson, M.S., and J.D. Molkentin. (2015). MBNL1-mediated regulation of pro-differentiation RNAs promotes myofibroblast transformation. Commun. 6:10084. doi: 10.1038/ncomms10084.
Corama, R.J., Stillwagona, S.J., Guggilama, A., Hazena, S.L., Jenkins, M.W., Swanson, M.S., and A.N. Ladd. (2015). Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev. Biol. 15:36-55.
Goodwin, M., Mohan, A., Batra, R., Lee, K-Y., Charizanis, K., Gómez, F.J.F., Eddarkaoui, S., Sergeant, N., Buée, L., Kimura, T., Clark, H.B., Dalton, J., Takamura, K., Weyn-Vanhentenryck, S., Zhang, C., Reid, T., Ranum, L.P.W., Day, J.W., and M. S. Swanson. (2015). MBNL sequestration by toxic RNAs and RNA mis-processing in the myotonic dystrophy brain. Cell Rep. 12:1159-1168.
Rau, F., Lainé, J., Ramanoudjame, L., Ferry, A., Arandel, L., Delalande, O., Jollet, A., Dingli, F., Lee, K-Y., Peccate, C., Lorain, S., Kabashi, E., Loew, D., Swanson, M.S., LeRhumeur, E., Dickson, G., Allamand, V., Marie, J., and D. Furling. (2015). Abnormal splicing switch of DMD penultimate exon compromises muscle fiber maintenance in myotonic dystrophy. Commun. 6:7205 | DOI: 10.1038/ncomms8205.
Batra, R., Manchanda, M., and M.S. Swanson. (2015). Global insights into alternative polyadenylation regulation. RNA Biol. 12:597-602.
Xia, G., Gao, Y., Jin, S., Subramony, S., Terada, N., Ranum, L.P., Swanson, M.S., and T. Ashizawa. (2015). Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 induced pluripotent stem-cell derived neural stem cells. Stem Cells 33:1829-1838.
Swanson, M.S. (2015). Rectifying RNA splicing errors in hereditary neurodegenerative disease. Natl. Acad. Sci. USA 112:2637-2638.
Batra, R., Charizanis, K., Manchanda, M., Mohan, A., Li, M., Finn, D.J., Goodwin, M., Zhang, C., Sobczak, K., Thornton, C.A., and M.S. Swanson. (2014). Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Cell 56:311-322.
Mohan, A., Goodwin, M., and M.S. Swanson. (2014). RNA-protein interactions in unstable microsatellite diseases. Brain Res., doi: 10.1016/j.brainres.2014.03.039. PMID: 24709120.
Goodwin M., and M.S. Swanson. (2014). RNA-binding protein mis-regulation in microsatellite expansion disorders. Exp. Biol. Med. 825:353-388.
Publications extracted from Pubmed
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