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  • Review Article
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Neuronal regulation of alternative pre-mRNA splicing

Nature Reviews Neuroscience volume 8, pages 819–831 (2007)Cite this article

Key Points

  • Alternative splicing is an important mechanism that regulates gene function in the nervous system, but is not well understood either mechanistically or for its roles in neuronal cell biology. Recent studies of the molecules that control splicing choices, and of the functions of alternatively spliced isoforms produced from important neuronal genes, have begun to clarify both of these issues.

  • The spliceosome must assemble onto each intron to catalyse its excision, and this assembly is controlled by a large number of pre-mRNA-binding proteins. Alternative splicing can produce many different kinds of insertions and deletions in the final mature mRNA, and these changes can drastically alter the function of the protein product.

  • Important genetic switches in splice-isoform expression occur at nearly every step in neuronal development, as well as in mature neurons. Developmental programmes of alternative splicing affect embryonic patterning, cell-fate determination, axon guidance and synaptogenesis.

  • In mature neurons, alternative splicing tunes the properties of many proteins that control cell excitation, including ion channels, the exocytosis apparatus and neurotransmitter receptors. Splicing alterations in these transcripts affect the excitation properties of the cell and contribute to long-term potentiation and other forms of neuronal plasticity.

  • Many exons in ion channel and neurotransmitter receptor transcripts are dynamically regulated by stimuli such as depolarization, bicuculin treatment and calcium/calmodulin dependent protein kinase IV (CaMKIV) activation. Regulatory RNA elements that mediate inducible splicing repression by depolarization and CaMKIV have been identified.

  • Alternative exons are controlled by combinations of regulatory proteins that bind to short sequence elements in the exon or its adjacent introns. Individual regulatory proteins can often mediate either splicing repression or enhancement, depending on the placement of their binding sites.

  • Proteins in the polypyrimidine tract-binding protein (PTB), Nova, Hu, CUG-binding protein and Fox families are known to regulate important neuronal exons. The target exon sets for the Nova, PTB and Fox proteins have been at least partially defined. For the NOVA2 protein, these targets include molecules that are needed for the LTP response of inhibitory postsynaptic currents in the hippocampus.

  • Most alternative exons are affected by repressor proteins in some cells and enhancer proteins in others. The splicing of alternative 5′ splice sites in the 5-hydroxytryptamine (5-HT) 2C receptor is also controlled by a small RNA, HBII-52, that is similar in structure to small nucleolar RNAs and that base pairs to a regulatory sequence in the exon.

  • Many important aspects of splicing regulation need to be better understood. These include the interactions of the regulatory proteins with the spliceosome and the larger functions of these regulators in development and physiology.

Abstract

Alternative pre-mRNA splicing has an important role in the control of neuronal gene expression. Many neuronal proteins are structurally diversified through the differential inclusion and exclusion of sequences in the final spliced mRNA. Here, we discuss common mechanisms of splicing regulation and provide examples of how alternative splicing has important roles in neuronal development and mature neuron function. Finally, we describe regulatory proteins that control the splicing of some neuronally expressed transcripts.

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Figure 1: Patterns of alternative splicing.
Figure 2: Alternative splicing of neurexins and neuroligins determines the assembly of excitatory or inhibitory synapses.
Figure 3: Splicing of APOER2 exon 19 regulates reelin-induced enhancement of LTP.
Figure 4: The alternative splicing of ion channel transcripts is dynamically regulated by calcium signalling pathways.
Figure 5: LTP of sIPSCs requires the splicing regulator NOVA2.
Figure 6: Alternative exons are controlled by multiple regulators.

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Acknowledgements

The authors would like to thank all the members of the Black laboratory and our other colleagues for many helpful discussions. We apologize to the numerous colleagues whose interesting splicing stories could not be included due to space constraints. Our own work is supported by grants RO1 GM049662 and R24 GM070857 from the US National Institutes of Health, by the Howard Hughes Medical Institute and by a 2007 Young Investigator Award to Q.L. from NARSAD: The Mental Health Research Association.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, University of California, Los Angeles, 6-762 MacDonald Research Laboratories, 675 Charles E. Young Drive South, Los Angeles, 90095, California, USA

    Qin Li & Douglas L. Black

  2. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 6-762 MacDonald Research Laboratories, 675 Charles E. Young Drive South, Los Angeles, 90095, California, USA

    Ji-Ann Lee & Douglas L. Black

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  1. Qin Li
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Glossary

Pre-mRNA

The unprocessed precursor to mRNA. It contains unspliced introns.

Exon

A segment of RNA that remains in the mRNA after intron removal. Pre-mRNA splicing results in the ligation of exons into a chain.

Intron

A segment of RNA that separates two exons in the pre-mRNA and is excised during splicing. Also called an intervening sequence.

Splice site

Short RNA sequences at exon–intron and intron–exon borders. They are bound by components of the spliceosome and encompass the nucleotides where the transesterification chemistry takes place.

Small nuclear ribonucleoprotein

(snRNP). A complex that is composed of a small nuclear RNA and a specific set of proteins.

Lariat RNA

A product of the first step of splicing, in which the 5′ phosphate of the 5′ terminal guanosine of the intron is linked to the 2′ hydroxyl of an adenosine residue that lies downstream at the branchpoint. This reaction creates a branched nucleotide that has an unusual 2′ to 5′ phosphodiester bond in addition to the normal 3′ to 5′ linkages, and an unusual loop-and-3′-tail structure, hence the name.

Exon cassette

An exon that has regulated splicing, and so can be included in the mRNA or skipped.

Expressed sequence tag (EST) analysis

Sequence comparisons of EST databases. When ESTs are aligned with each other, and with mRNA and genomic sequences, regions of alternative processing can be identified.

Asymmetrical division

A mitotic division that generates daughter cells that have different cell fates.

SNARE

Soluble NSF (N-ethylmaleimide-sensitive fusion protein) accessory protein (SNAP) receptor.

Nociceptive neurons

(Also known as nociceptors.) Pain-sensitive cells that carry information about tissue damage from the body's periphery to synapses in the dorsal horn of the spinal cord.

Kindling

An experimental model of epilepsy in which an increased susceptibility to seizures arises after daily focal stimulation of specific brain areas (for example, the amygdala) — stimulation that does not by itself reach the seizure-causing threshold.

Homeostatic plasticity

Activity-dependent changes in synaptic strength that tend to stabilize neuronal firing rates.

Heterogeneous nuclear ribonucleoprotein

(hnRNP). A protein that binds to nascent RNA polymerase II transcripts and packages pre-mRNAs into hnRNP-containing particles in the nucleus. hnRNPs have a variety of RNA-binding domains and function in various processes, including nuclear splicing, polyadenylation and export, as well as cytoplasmic mRNA translation and turnover.

SR proteins

A family of splicing regulatory proteins that bind to exonic splicing enhancer elements to stimulate exon inclusion. They contain one or more domains rich in serine (S)–arginine (R) dipeptides and one or more RNA-binding domains.

RNA editing

Site-specific modification of mRNA sequences after transcription. The most common modification is the conversion of adenosine to inosine by adenosine deaminase enzymes (ADARs) — a conversion that changes the coding capacity of the affected mRNA.

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Li, Q., Lee, JA. & Black, D. Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci 8, 819–831 (2007). https://doi.org/10.1038/nrn2237

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