SMNdeficiency altersNrxn2expression and splicing in zebrafish and mouse models of spinal muscular atrophy


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Abstract

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease affecting lower motor neurons. SMA is caused by mutations in theSurvival Motor Neuron 1(SMN1) gene, which result in reduced levels of functional SMN protein. Biochemical studies have linked the ubiquitously expressed SMN protein to the assembly of pre-mRNA processing U snRNPs, raising the possibility that aberrant splicing is a major defect in SMA. Accordingly, several transcripts affected upon SMN deficiency have been reported. A second function for SMN in axonal mRNA transport has also been proposed that may likewise contribute to the SMA phenotype. The underlying etiology of SMA, however, is still not fully understood. Here, we have used a combination of genomics and live Ca2+ imaging to investigate the consequences of SMN deficiency in a zebrafish model of SMA. In a transcriptome analyses of SMN-deficient zebrafish, we identifiedneurexin2a(nrxn2a) as strongly down-regulated and displaying changes in alternative splicing patterns. Importantly, the knock-down of two distinctnrxn2aisoforms phenocopies SMN-deficient fish and results in a significant reduction of motor axon excitability. Interestingly, we observed altered expression and splicing ofNrxn2also in motor neurons from theSmn−/−;SMN2+/+mouse model of SMA, suggesting conservation ofnrxn2regulation by SMN in mammals. We propose that SMN deficiency affects splicing and abundance ofnrxn2a. This may explain the pre-synaptic defects at neuromuscular endplates in SMA pathophysiology.

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