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The neurogenetics of alternative splicing

Nature Reviews Neuroscience volume 17, pages 265–281 (2016)Cite this article

Subjects

Key Points

  • Dysregulation of splicing, an emerging cause of many neurological disorders, affects all aspects of neurobiology from neurogenesis to synaptic function.

  • The interplay between polypyrimidine tract binding protein 1 (PTBP1), serine/arginine repetitive matrix protein 4 (SRRM4), miR-124 and the REST (repressor element 1-silencing transcription factor) complex constitutes an important genetic programme underlying neuronal cell fate commitment.

  • Neuronal migration during development requires cell surface receptor isoforms, the splicing of which is controlled by neuro-oncological ventral antigen 2 (NOVA2) and RNA-binding protein fox-1 homologue 2 (RBFOX2).

  • The PTBP, SRRM4 and NOVA proteins orchestrate developmental synapse formation.

  • Many splicing regulators, including KH domain-containing, RNA-binding, signal transduction-associated (KHDRBS) proteins, NOVA2 and muscleblind-like 2 (MBNL2), modulate synaptic transmission and plasticity.

  • RBFOX1 and neuronal ELAV-like (nELAVL) regulate neuronal excitability.

  • Understanding the biological roles of neuronal splicing regulators is challenged by extensive target sets, pleiotropic phenotypes and partial redundancy of paralogous regulators.

  • Mutations in both protein regulators and core RNAs of the spliceosome can lead to neurodegenerative disorders.

Abstract

Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation of splicing is implicated in multiple neurological disorders. We describe recent mouse genetic studies of alternative splicing that reveal its critical role in both neuronal development and the function of mature neurons. We discuss the challenges in understanding the extensive genetic programmes controlled by proteins that regulate splicing, both during development and in the adult brain.

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Figure 1: Splicing regulatory networks.
Figure 2: Splicing regulators in cortical development and function.
Figure 3: Splicing regulators in cerebellar development and function.
Figure 4: Alternative splicing regulation of synaptogenesis and synaptic function.
Figure 5: Regulatory outcomes of RNA-binding proteins.

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Acknowledgements

The authors thank researchers in the laboratory of D.B., the laboratory of S.Z. and other colleagues for many helpful discussions. Their work is supported by the US National Institutes of Health grants R01 GM49662 to D.B., K99 MH096807 to S.Z. and F31 NS093923 to C.V.

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Authors and Affiliations

  1. Molecular Biology Interdepartmental Graduate Program, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Celine K. Vuong

  2. Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, 90095, California, USA

    Douglas L. Black

  3. Division of Biomedical Sciences, University of California at Riverside, Riverside, 92521, California, USA

    Sika Zheng

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  1. Celine K. Vuong
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Correspondence to Douglas L. Black or Sika Zheng.

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Supplementary information

Supplementary information S1 (table)

Properties of Proteins and RNAs discussed in this review (PDF 503 kb)

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Glossary

Spliceosome

A large macromolecular assembly of small nuclear ribonucleoproteins and proteins that catalyses the excision of introns from precursor mRNAs.

Pleiotropy

A condition where one gene can influence multiple phenotypic traits.

Paralogues

Related genes within a genome that often arise from gene duplication during evolution.

Polypyrimidine tract

A sequence element located between the branch point and the 3′ splice site that is bound by U2AF during normal spliceosome assembly; it is also a binding site for the polypyrimidine tract binding protein that can be found elsewhere in the precursor mRNA.

3′ splice site

The sequence at the 3′ end of the intron that is recognized by the U2AF protein component of the spliceosome. Also called an acceptor site.

YCAY elements

Sequences consisting of a cytosine (C) and an adenine (A) flanked by two pyrimidines (Y).

5′ splice site

The sequence at the 5′ end of the intron that is recognized by the U1 small nuclear ribonucleoprotein component of the spliceosome. Also called a donor site.

Branch point

An intronic sequence element upstream from the polypyrimidine tract of the 3′ splice site where a branched nucleotide at a specific adenosine will be formed by the first transesterification step of splicing. The branch point is recognized by the U2 small nuclear ribonucleoprotein.

Major class introns

Also called GT/AG introns, which are excised by the major spliceosome containing the U1 and U2 small nuclear ribonucleoproteins.

CLIP–seq

(Crosslinking immunoprecipitation followed by high-throughput sequencing). A method used to identify the binding sites of RNA-binding proteins across the transcriptome.

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Vuong, C., Black, D. & Zheng, S. The neurogenetics of alternative splicing. Nat Rev Neurosci 17, 265–281 (2016). https://doi.org/10.1038/nrn.2016.27

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