Key result
Depletion of hnRNP R or suppression of its top RNA interactor, 7SK, led to defective axon growth and axonal transcriptome alterations in motoneurons.
The noncoding RNA 7SK is an essential interactor of hnRNP R that regulates its function in axon maintenance, providing insights into motoneuron disease pathomechanisms.
May inform axonal RNA targets in ALS/SMA; leaves open functional validation before any clinical consideration.
Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms by which they regulate the subcellular diversity of transcriptomes, particularly in axons, are not understood. Heterogeneous nuclear ribonucleoprotein R (hnRNP R) interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons, and its depletion causes defects in axon growth. Here, we used individual nucleotide-resolution cross-linking and immunoprecipitation (iCLIP) to determine the RNA interactome of hnRNP R in motoneurons. We identified ∼3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the noncoding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus and also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R, and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK-deletion mutants, we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the PTEF-B complex involved in transcriptional regulation. These results propose a role for 7SK as an essential interactor of hnRNP R to regulate its function in axon maintenance.
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Briese et al. (2018) studied Motoneuron diseases. hnRNP R and 7SK depletion was evaluated on RNA interactome of hnRNP R and axon growth. Depletion of hnRNP R or suppression of its top RNA interactor, 7SK, led to defective axon growth and axonal transcriptome alterations in motoneurons.
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