CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

摘要

Nerve cells or neurons carry information around the body along projections known as axons. An injury or trauma, such as a stroke, can damage the axons and lead to permanent disability because the damaged axons fail to regenerate over long distances. Axon damage triggers large changes in the activity of many genes that promote regeneration. When a gene is active, its DNA is copied to make molecules of messenger RNA (mRNA), which are then used as templates to make proteins. Many mRNAs undergo a process called alternative splicing, in which different combinations of mRNA sections may be removed from the final molecule. This enables a single gene to produce more than one type of protein. Recent studies point to an important role for so-called RNA binding proteins in regulating the alternative splicing process. An RNA binding protein called UNC-75 in a worm known as Caenorhabditis elegans has previously been shown to be involved in axon regeneration, but it was not clear how UNC-75 acts on neurons. Here, Chen et al. combined a technique called CLIP-seq (Cross-linking ImmunoPrecipitation-deep sequencing) with genetic testing to identify the mRNAs that UNC-75 regulates during axon regeneration. The experiments found a set of C. elegans genes required for information to pass between neurons whose mRNAs are also targeted by UNC-75. Many of these genes are also required for axon regeneration. Chen et al. studied one of the mRNA targets – which encodes a protein called syntaxin – in more detail and found that the syntaxin mRNA is required for regenerating axons over long distances. UNC-75 alternatively splices this mRNA to produce a particular form of syntaxin that is mainly found in neurons. Mutant worms that lack either UNC-75 or syntaxin are unable to properly regenerate axons over long distances. Further experiments show that a mouse protein known as CELF2 that is equivalent to worm UNC-75 plays a similar role in regenerating axons. Moreover, mouse CELF2 restores the ability of worm neurons that lack UNC-75 to regenerate. Like worm UNC-75, the mouse protein is also involved in alternative splicing of syntaxin. The next step is to examine the other mRNA targets of UNC-75 to find out what role they play in axon regeneration and other processes in neurons.