Neuronal cell-type-specific alternative splicing: A mechanism for specifying connections in the brain?

Joshua Shing Shun Li, Grace Ji-eun Shin, S Sean Millard
2015 Neurogenesis  
A lternative splicing (AS) allows a single gene to generate multiple protein isoforms. It has been hypothesized that AS plays a role in brain wiring by increasing the number of cell recognition molecules necessary for forming connections between neurons. Many studies have characterized isoform expression patterns of various genes in the brain, but very few have addressed whether specific isoforms play a functional role in neuronal wiring. In our recent work, we reported the cell-type-specific
more » ... of the cell recognition molecule Dscam2. Exclusive expression of Dscam2 isoforms allows tightly associated neurons to signal repulsion selectively within the same celltypes, without interfering with one another. We show that preventing cellspecific isoform expression in 2 closely associated neurons disrupts their axon terminal morphology. We propose that the requirement for isoform specificity extends to synapses and discuss experiments that can test this directly. Factors that regulate Dscam2 cell-type-specific AS likely regulate the splicing of many genes involved in neurodevelopment. These regulators of alternative splicing may act broadly to control many genes involved in the development of specific neuron types. Identifying these factors is a key step in understanding how AS contributes to the brain connectome. In 1978, Walter Gilbert postulated that, through RNA splicing, multiple proteins of related or diverging functions could potentially arise from only a single transcription unit. 1 Accordingly, this idea was validated by the discovery that both a secreted and a membrane-bound form of an antibody were being produced from a single gene. 2-5 Since then, more examples of the same phenomena have emerged and this mechanism is what we now refer to as alternative splicing (AS). More recent studies indicate that approximately 95% of human multi-exon genes are alternatively spliced. 6,7 AS remains a crucial mechanism for increasing proteome diversity, but little is known about its functional implication. Proteome diversity is much needed in the nervous system where multifaceted cellular processes, such as neurotransmission and synaptic plasticity, are coordinated with only a modest number of genes. It is also unclear how this limited set of genes specifies »10 15 neuronal connections that are found in the human brain. Neurodevelopmental studies conducted over the past few decades have elegantly uncovered protein-protein interactions that govern neuronal connectivity. 8,9 Among these are families of genes that generate extreme biochemical diversification of receptor isoforms through alternative promoter usage, AS or a combination of the 2. [10] [11] [12] [13] Two dramatic examples of this are the mammalian clustered protocadherins and Drosophila Dscam1. Both genes produce multiple isoforms with unique binding specificities, whereby identical isoforms mediate homophilic recognition. 14,15 If this diversity were required for specifying neuronal connections, one would expect isoform expression to be invariable between different animals. Contrary to this, the expression profile of single neurons revealed that numerous isoforms of both protocadherins and Dscam1 are expressed stochastically in each cell. [16] [17] [18] [19] This type of probabilistic isoform expression is not suited for specifying connections between different neurons, but rather establishes a
doi:10.1080/23262133.2015.1122699 pmid:27606331 pmcid:PMC4973604 fatcat:i5hy3unhorcwrllyu52gf2x7ga