Neurodevelopmental consequences of Smn depletion in a mouse model of spinal muscular atrophy

Abstract

Deletions or mutations in survival of motor neuron 1 (SMN1) cause motor neuron loss and spinal muscular atrophy (SMA), a neuromuscular disorder, with the most severe type manifesting in utero. Whether SMA is a disease of defects in neurodevelopment and/or neuromaintenance remains unclear. We performed an analysis of Smn gene and protein expression during murine embryogenesis. Furthermore, we examined Smn(-/-);SMN2 mice, a model of very severe SMA, for developmental, morphological, and molecular abnormalities. We demonstrate that Smn transcript levels are regulated in a tissue- and developmental stage-specific manner and that the Smn protein expression pattern generally followed that of the Smn mRNA. Cell death and pathological foci were observed in E10.5 Smn-depleted embryos, and this increased in the telencephalon at E14.5. Furthermore, we show an altered morphology of cranial nerves as well as truncated lumbar spinal nerves in a subset of E10.5 Smn(-/-);SMN2 embryos. Finally, we compared the splicing of a subset of genes shown recently to be aberrantly spliced in phenotypic-stage SMA mice. Changes in alternative splicing of the Slc38a5 and Uspl1 genes were detectable in prephenotypic-stage embryos and neonates but became more pronounced with the severity of the phenotype. By comparison, Hif3a alternative splicing was affected only at the end stage of disease. This result suggests that alterations in mRNA splicing in SMA occur, in part, as a result of disease progression. Overall, we conclude that Smn depletion affects developmental processes, which ultimately may also contribute to SMA pathogenesis.

Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

“…Equivalent suggestions have been proposed for the role of TDP-43 and FUS in ALS [168]. However, as discussed above, recent reports from experiments on mouse models of SMA imply the splicing defects observed in SMA are present at only modest degrees and are progressive with pathology, indicating they occur as a result, rather than cause, of motor neurone degeneration [91,171]. Thus, it appears that splicing defects are, in themselves, not likely to cause early vulnerability of synapses and trigger neuromuscular pathology in SMA.…”

ChondrolectinMediates Growth Cone Interactions of Motor Axons with an Intermediate Target

“…Using exon profiling in mouse models of SMA, specific isoform changes for chodl have been found already at early symptomatic stages, whereas most genes were dysregulated only at late symptomatic stages (Zhang et al, 2008;Bäumer et al, 2009). Reduced expression of SMN leads to shorter mouse motor axons in vitro (Rossoll et al, 2003), and one of the phenotypes in developing zebrafish (McWhorter et al, 2003) and mice (Liu et al, 2010) is also shorter axons. Thus, part of the phenotypes could be mediated through altered chodl expression, which when missing also leads to arrested or delayed motor axon growth, as we show here.…”

Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

“…Furthermore, the reduction of sensory input into lumbar motor neurons was also observed in the Olig2-Cre mouse even when the sensory neurons did not have reduced SMN protein . The reduction of SMN protein also has consequences for neuronal growth and development as evidenced by reduced neuronal numbers in the brain and eye of severe SMA mouse models Line89 and Smn 2B (Liu et al 2010;Wishart et al 2010). The modelling of SMA in mice have recapitulated the motor neuron loss as is seen in SMA patients, as well as identified neuronal populations affected by reduced SMN levels in the SMA mouse models.…”