Gloria Vittone Echeverria
Ph.D. Student, Inter-institutional Program in Cell and Molecular Biology
Funding: NSF Graduate Research Fellowship Award
Started in the lab: July 2009
I am interested in understanding the mechanism by which a splicing regulatory protein, Muscleblind-like 1 (MBNL1), to activate alternative splicing. MBNL1 regulates hundreds of splicing events during vertebrate postnatal development. Many of these events are disrupted in myotonic dystrophy (DM), in which MBNL1 is sequestered on RNA containing expanded CUG or CCUG repeats. MBNL1 activates inclusion of exon 11 of the insulin receptor (IR) pre-mRNA, an event that is known to be disrupted in DM. My project focuses on determining the biochemical mechanism by which MBNL1 activates recognition of IR exon 11 by the basal splicing machinery (the spliceosome). Previous studies have determined that MBNL1 binds an intronic enhancer 90 nucleotides downstream of IR exon 11. We have developed an in vitro splicing assay that recapitulates MBNL1-activated IR exon 11 inclusion and have shown that MBNL1 promotes recognition of exon 11 by the spliceosome. We have demonstrated that MBNL1 binding in the downstream intron promotes assembly of splicing complexes across the exon, resulting in removal of the upstream intron. Our current studies are focused on identifying the splicing complex that responds to MBNL1 and direct MBNL1-interacting proteins involved in this process.
Echeverria, G. V. and Cooper, T. A. (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Research 1462, 100-111.
Grammatikakis I., Goo Y., Echeverria G.V., and Cooper T.A. (2011). Identification of MBNL1 and MBNL3 domains required for alternative splicing activation and repression. Nucleic Acids Research. 39(7):2769-80.
Djonovic, S., Vittone, G., Mendoza-Herrera, A., and Kenerley, C.M. (2007). Enhanced biocontrol activity of Trichoderma virens transformants constitutively coexpressing β-1,3- and β-1,6-glucanase genes. Molecular Plant Pathology 8, 469-480.