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SMA, spinal muscular atrophy. ANIMAL MODELS OF SPINAL MUSCULAR ATROPHY Various SMA animal models have been produced and characterized, including Caenorhabditis elegans, Drosophila, zebrafish, mice, and pigs, in order to understand basic SMA pathology, determine the target tissues and the time window for effective treatment, identify disease-modifying genes and pathways, and validate therapeutic approaches at a preclinical stage. As each of these animals has only one Smn gene in its genome, none of them naturally develop SMA. Different approaches have been used to overcome this problem, including conditional Smn knockout, introduction of the human SMN2 gene, or introduction of splice or missense mutations (46 and references therein). In the following sections, we discuss the animal models and their contributions to our knowledge of SMA (Figure 3). Unraveling the Pathophysiology of Spinal Muscular Atrophy As SMN is a crucial protein for cell survival, mice with complete Smn deletion fail to develop during the early stages of embryogenesis (155). Numerous mouse models have been produced to recapitulate SMA phenotypes by introducing human SMN2 and/or SMN7 (75, 99, 126). These mouse models showed short survival (6–14 days), impaired motor function, loss of spinal motor neurons, and defects in NMJs and muscle tissues (reviewed in 62 and references therein). They have been used to identify defects in RNA metabolism, protein synthesis, endocytosis, protein homeostasis, the actin cytoskeleton, and Ca2+ homeostasis (71, 83, 98, 186, 192). Interestingly, the leading cause of early death in SMA mice might be severe impairment of internal organs, including the lung, heart, pancreas, intestine, vessels, and bones, suggesting that other organs or tissues contribute to SMA pathology (reviewed in 66 and references therein). 242 Wirth et al. Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. Zebrafish SMA models have been used to visualize motor neuron morphology in vivo. SMN protein in zebrafish has a 66% similarity with human SMN (16). Because SMN deficiency in zebrafish causes defects in axonal outgrowth and pathfinding of motor neurons, they have been actively used to identify pathomechanisms and to validate the effect of genetic modifiers (84, 111, 129, 142, 179). Determining the Target Tissues and the Time Window for Effective Treatment Transgenic mice with tissue-specific modifications of SMN levels have been generated to identify additional contributors to SMA pathology. First, motor neuron–specific SMN-deficient mice survived 25 days with severe motor impairment (56). Second, muscle-specific deletion of exon 7 caused muscle atrophy, suggesting that SMN is indispensable for muscle (28). However, a tissuespecific deletion and replacement study showed that SMN proteins produced from two copies of SMN2 might be sufficient for healthy muscle function, suggesting that muscle requires less SMN than motor neurons do (82). Third, liver-specific SMN loss (only with Smn7) caused neonatal lethality with severe defects in liver development, while patients with two copies of SMN2 did not show any sign of liver dysfunction, suggesting that the liver requires relatively less SMN (177). Thus, complete Smn knockout in any organ is detrimental, given the housekeeping role of SMN in snRNP biogenesis and splicing. While SMN levels below 15–20% in mice seem to cause internal organ impairment, levels above 20–25% impair only motor neuron function. Knowledge from mouse models strongly suggests that different cell types have different levels of susceptibility to SMN deficiency and that restoring SMN levels in peripheral tissues and internal organs will be necessary for SMA patients (162). Even in the nervous system, it seems that motor neurons are not the only ones affected by SMA. Defects in proprioceptive sensory neurons have been reported together with defects in spinal circuitry (115). Whether the impairment of sensory neurons is due to intrinsic defects or is a consequence of
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