Neuronal regulation of alternative pre-mRNA splicing

Abstract

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.