The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation.

Qin Li,Chia-Ho Lin,Areum Han,Sika Zheng,Peter Stoilov,Xiang-Dong Fu,Douglas L Black

doi:10.7554/elife.01201

Abstract

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.

Highlights

Compared to other cells, neurons undergo an unusually long period of maturation as they differentiate
Alternative pre-messenger RNA splicing is a common mechanism for genetic control in the nervous system, where many proteins important for neuronal differentiation and function are made in diverse isoforms through changes in splice site choice (Licatalosi and Darnell, 2006; Li et al, 2007; Norris and Calarco, 2012; Yap and Makeyev, 2013; Zheng and Black, 2013)
We show that the loss of PTBP2 leads to a catastrophic failure in neuronal maturation and to the misexpression of many protein isoforms affecting neurite growth, synapse formation and synaptic transmission

Summary

Introduction

Neurons undergo an unusually long period of maturation as they differentiate. A wide variety of genetic mechanisms ensure that these events occur in proper sequence and induce cell death when a process is incorrect. This developmental pathway is best understood at the level of transcriptional regulation where important signaling molecules, transcription factors, and epigenetic modifications are implicated in lineage commitment, cell survival, and establishment of synaptic connections. Alternative pre-messenger RNA splicing is a common mechanism for genetic control in the nervous system, where many proteins important for neuronal differentiation and function are made in diverse isoforms through changes in splice site choice (Licatalosi and Darnell, 2006; Li et al, 2007; Norris and Calarco, 2012; Yap and Makeyev, 2013; Zheng and Black, 2013).

Methods

Results

Conclusion