Alternative RNA splicing
Dr. Grabowski received her Ph.D. in 1983 with Tom Cech at the University of Colorado, performed her postdoctoral studies with Philip Sharp at the Massachusetts Institute of Technology, and joined the Department in 1991.
Alternative pre-messenger RNA splicing generates widespread transcript diversity by specifying the inclusion or exclusion of sequences encoding protein functional domains. We are interested in understanding how these mechanisms are coordinated in the nervous system to tailor the structures of protein molecules for their specific roles at the synapse relating to neuronal communication and plasticity.
Current studies in the lab are focused on the mechanisms by which splicing decisions respond to neuronal stimulation. Calcium imaging and biochemical approaches are underway to understand how signaling from the membrane to the nucleus regulates key functions of splicing factors to induce changes in alternative splicing patterns. A complementary approach uses RNA fluorescence in situ hybridization to probe the dynamic associations of splicing factors with nascent mRNA transcripts in vivo. We are extending this analysis genome wide to identify the splicing codes involved in the inducible regulation of diverse splicing events. Additional projects in the lab involve the analysis of the effects of viral infection on alternative splicing of host cell transcripts using Next Generation Sequencing Approaches. The results of these studies will impact our understanding of the mechanisms by which the plasticity of splicing can be modulated by cellular events, and how imbalances in its fine-tuned regulation can contribute to the development of human disease.
Dembowski JA, An P, Scoulos-Hansen M, Yeo G, Han J, Fu XD, and PJ Grabowski (2012) Alternative splicing of a novel inducible exon diversifies the CASK guanylate kinase domain. J. Nucleic Acids. 2012.2012:816237
Grabowski, P. (2011) Alternative splicing takes shape during development. Curr Opin Genet Dev. 21:388-94
Dembowski, J.A., and P.J. Grabowski (2009) The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS Genet. 5:e1000595e1000
Grabowski, P.J. (2007) RNA-binding proteins switch gears to drive alternative splicing in neurons. Nat. Struct. Mol. Biol. 14:577-579
An, P., and P.J. Grabowski (2007) Exon silencing by UAGG motifs in response to neuronal excitation. PLoS Biol. 5:e36
Grabowski, P.J. (2005) Splicing-active nuclear extracts from rat brain. Methods 37:323-330
Xu, X.M., H. Mix, B.A. Carlson, P.J. Grabowski, V.N. Gladyshev, M.J. Berry, and D.L... Hatfield (2005) Evidence for direct roles of two additional factors, SECp43 and SLA, in the selenoprotein synthesis machinery. J. Biol. Chem. 280:568-575
Han, K., G. Yeo, P. An, C.B. Burge, and P.J. Grabowski (2005) A combinatorial code for splicing silencing: UAGG and GGGG motifs. PLoS Biol. 3:e158
Grabowski, P.J. (2004) A molecular code for splicing silencing: configurations of guanosine-rich motifs. Biochem. Soc. Trans. 32:924-927
Miné, M., M. Brivet, G. Touati, P. Grabowski, M. Abitbol, and C. Marsac (2003) Splicing error in E1alpha pyruvate dehydrogenase mRNA caused by novel intronic mutation responsible for lactic acidosis and mental retardation. J. Biol. Chem. 278:11768-11772
Black, D.L., and P.J. Grabowski (2003) Alternative pre-mRNA splicing and neuronal function. Prog. Mol. Subcell. Biol. 31:187-216
Grabowski, P. (2002) Alternative splicing in parallel. Nat. Biotechnol. 20:346-347
Zhang, W., H. Liu, K. Han, and P.J. Grabowski (2002) Region specific alternative splicing in the nervous system: implications for regulation by the RNA binding protein, NAPOR. RNA 8:671-685
Wu, J.I., R. Reed, P.J. Grabowski, and K. Artzt (2002) The function of quaking in myelination: Regulation of alternative splicing. Proc. Natl. Acad. Sci., USA 99:4233-4238
Liu, H., W. Zhang, R. Reed, W. Liu, and P.J. Grabowski (2002) Mutations in RRM4 uncouple the splicing repression and RNA-binding activities of polypyrimidine tract binding protein. RNA 8:137-149
Grabowski, P.J., and D.L. Black (2001) Alternative RNA splicing in the nervous system. Prog. Neurobiol. 65:289-308