Diversity in the proteome is achieved in several ways, including the regulation of pre-mRNA splicing and polyadenylation. Most pre-mRNA processing is thought to happen in the nucleus of cells but numerous splicing regulators can be found in neurites although we know little about their activity.
In a new publication from Nikolas Nikolaou and the Makeyev and Houart labs, the authors investigate the non-nuclear role of SNRNP70, a major spliceosome protein. Nikolaou et al., published in Current Biology , show for the first time that non-nuclear SNRNP70 is essential to motor function and regulates neuronal connectivity through the modulation of mRNA stability, processing, and axonal trafficking.
In an elegant series of experiments using zebrafish, Nikolaou et al. first looked at the distribution of SNRNP70 and found the protein not only in the cell body but in RNA-associated granules in axons too. An SNRNP70 mutant line deficient in the protein had motor connectivity defects and a loss of motor function. When SNRNP70 was restored in only non-nuclear areas in the mutant, the partial rescue was sufficient to cluster acetylcholine receptors, a process crucial to establishing neuron to muscle connectivity. Finally, Nikolaou et al. sought to determine if SNRNP70 is involved in RNA processing as the protein is both RNA-binding and a splicing protein. The authors found that indeed this was the case and saw expression changes in thousands of genes, including many involved in motor function, in the mutant model. Interestingly, the non-nuclear rescue was sufficient to restore the expression of many of these genes.
SNRNP70 has previously been associated with neurodegenerative disorders including Alzheimer’s disease and amyotrophic lateral sclerosis. Nikolaou et al. demonstrate a critical role for the protein in motor function and shed new light on the function of a splicing protein implicated in neurodegeneration.
Nikolas Nikolaou, Patricia M. Gordon, Fursham Hamid, Richard Taylor, Joshua Lloyd-Jones, Eugene V. Makeyev, Corinne Houart. (2022). Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity. Current Biology