title: PTBP1 and PTBP2 Serve Both Specific and Redundant Functions in Neuronal Pre-mRNA Splicing.
abstract: Families of alternative splicing regulators often contain multiple paralogs presumed to fulfill different functions. Polypyrimidine tract binding proteins PTBP1 and PTBP2 reprogram developmental pre-mRNA splicing in neurons, but how their regulatory networks differ is not understood. To compare their targeting, we generated a knockin 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. 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.
authors.affiliation: Division of Biomedical Science, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Vuong
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Chia-Ho
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Division of Biomedical Science, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dougb@microbio.ucla.edu.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Black
authors.affiliation: Division of Biomedical Science, University of California, Riverside, Riverside, CA 92521, USA. Electronic address: sikaz@ucr.edu.
authors.forename: Sika
authors.initials: S
authors.lastname: Zheng
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; C573992:Ptbp1 protein, mouse; C429773:Ptbp2 protein, mouse; D012322:RNA Precursors; D038941:Polypyrimidine Tract-Binding Protein
keywords: CLIP; GeneSplice; PTBP1; PTBP2; RNA binding proteins; RNA-seq; alternative splicing; brain development; neuronal differentiation; splicing reprogramming