The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation.
We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2(-/-) neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron. DOI: http://dx.doi.org/10.7554/eLife.01201.001.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
Qin
Q
Li
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
Sika
S
Zheng
Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, United States.
Areum
A
Han
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
Chia-Ho
CH
Lin
Department of Biochemistry, West Virginia University, School of Medicine, Morgantown, United States.
Peter
P
Stoilov
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States.
Xiang-Dong
XD
Fu
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.|Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
Douglas L
DL
Black
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology*; D009474:Neurons / Q000502:physiology; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D017422:Sequence Analysis, DNA
D009419:Nerve Tissue Proteins; C429773:Ptbp2 protein, mouse; D038941:Polypyrimidine Tract-Binding Protein
RNA binding protein; alternative splicing; gene regulation; neuronal development