Neuron-specific regulation of alternative pre-mRNA splicing
4th International Congress on Drug Discovery, Designing and Development & International Conference and Exhibition on Biochemistry, Molecular Biology: R&D
November 02-03, 2017 Chicago, USA
University of California, Riverside, USA
Scientific Tracks Abstracts : J Pharmacol Ther Res
Families of alternative splicing regulators often contain multiple paralogs presumed to fulfill different functions. Polypyrimidine tract binding proteins Ptbp1 and Ptbp2 exhibit dynamic stage-specific expression and program developmental pre-mRNA splicing in neurons, but how and why their regulatory actions differ are not understood. To compare their targeting, we generated a knockin mouse allele that conditionally expresses Ptbp1. Bred to a Ptbp2 knockout, the transgene allowed us to compare the developmental and molecular phenotypes of mice expressing only Ptbp1, only Ptbp2, or neither protein in the brain. This knockin Ptbp1 rescued a forebrain-specific, but not a pan-neuronal, Ptbp2 knockout, demonstrating both redundant and distinct roles for the proteins. Using comprehensive approaches of biochemistry, RNA-Seq, and CLIP-Seq to probe their targeting and protein-RNA interactions, we found that many developmentally regulated exons exhibited different sensitivities to Ptbp1 and Ptbp2. Nevertheless, the two paralogs displayed similar RNA binding across the transcriptome, indicating that their differential targeting does not derive from their RNA interactions, but from possible different cofactor interactions.
Sika Zheng is an expert in studying RNA binding proteins and alternative splicing. His lab combines Biochemistry, Molecular Biology, Cell Biology, Neurobiology, Genetics, Genomics, and Computational Biology to understand the activity, mechanism, function and dysfunction of gene regulation at the RNA level in the nervous system focusing on Ptbp1 and Ptbp2 two RNA binding proteins programming neuron-specific alternative splicing. He has made seminal contributions revealing the roles of alternative splicing for neuronal development and the mechanisms of Ptbp1/2 controlling neuron-specific alternative splicing events.