Precise temporal regulation of alternative splicing during neural development

Background

Alternative splicing is a well-appreciated mechanism for generating protein isoform diversity from a set of genes. The brain is an organ particularly rich with alternatively spliced transcripts, but how and why RNA-binding proteins control alternative splicing dynamics during development of the brain is only beginning to be understood.

 Key findings

In the latest salvo from the lab of Chaolin Zhang, the team classified and profiled alternative splicing during mammalian brain development at unprecedented scale. Some of the numbers presented here are mind-blowing (pun intended) – for example, they found that a third of all expressed genes change their splicing patterns during cortex development. For this reader, the paper gets really interesting when the authors correlated the expression of RNA binding proteins (RBPs) and their massive catalog of alternative splicing events. Looking at a set of four RBP families known to be involved in alternative splicing (Ptbp, Nova, Rbfox, and Mbnl), the authors provide striking evidence that the dynamic expression of these RBPs drives large changes in splicing during neuronal development. Extending these data, they suggest that combinatorial expression of these RBPs defines a splicing code that determines neuronal maturation during development.

Of course outliers are often the most interesting parts of research, and here was no exception. Most samples they looked at had splicing patterns that correlate well with developmental stage, but sensory neurons refused to conform. Sensory neurons from an adult mouse had the splicing patterns of embryonic neurons. The switch to the mature splicing state never happens! As it turns out, sensory neurons never express Rbfox or Nova, and so these cell types have none of the splicing dependent on these factors. Since embryonic CNS neurons and sensory neurons both have regenerative capacity which is lost in mature CNS neurons, the authors hint at an provocative hypothesis that youthful splicing patterns might aid in neural regeneration.

Future directions

The authors are poised to understand how important these dynamic splicing patterns are to cell fate and function. This reader was struck by three of many possible future directions.

1. Regeneration. Can we reset splicing dynamics to improve adult neuron regeneration, and what splicing events are driving that function?
2. Other factors. While these four RBP families appear to drive the majority of splicing dynamics, what about the hundreds of other RBPs which are differentially expressed in the brain? How might they wire RNA splicing (or decay, localization, etc)? Are they also tuning neuronal function at certain times or regions of the brain?
3. Zoom in. One could apply this approach to single-cell RNA sequencing atlases of brain development. While there are technical limitations – notably the shallow depth and 5’ and 3’ end biases of current sequencing methods – there may be a hidden universe of splicing control of neuronal maturation and development in certain cell types.

Tags: neurodevelopment, neurons, rbps, rna binding proteins, sensory neurons, splicing

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