Paula Grabowski

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.

Recent Publications

• 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