Figure 5.

Hb9-Cre rescues motor unit pathology in SMA mice. A–C, At end stage, MN-rescued SMA NMJs within the ICs were indistinguishable from controls in innervation status and endplate maturity (n = 6 per genotype, >50 NMJs per mouse). D, E, NMJs within the TS of MN-rescued SMA mice showed no difference in innervation and demonstrated only a variable delay in postsynaptic maturity (n = 3 per genotype, >50 NMJs per mouse; p = 0.04; 2-way ANOVA, Bonferroni's post-test). F, G, Severe inducible SMA mice had a significant reduction in the average number of ChAT and Islet-1 double-positive MNs per ventral horn within cervical (C4–C8), thoracic (T8–T11), and lumbar (L2–L5) spinal cord (p = 0.01, p = 0.04, and p = 0.05, respectively). In contrast, MN-rescued SMA mice showed no loss in MNs in cervical and thoracic spinal segments, and had only a significant loss at the lumbar level, where Hb9-Cre expression is incomplete. Black, Control; red, SMA; purple, MN-rescue SMA. H, I, MN-rescued SMA mice did not differ from controls in average number of lumbar MMC neurons and showed a significant 25 ± 9% (p = 0.04) reduction in LMC neurons. A significant decrease in both MMC (−47 ± 12%; p = 0.05) and LMC (−29 ± 10%; p = 0.04) neurons was observed in severe inducible SMA mice (Student's t test). J, Confocal images of P5 L2–L5 motor neurons. vGlut1 labels the synapses (green), and the postsynaptic MN is marked by ChAT (red; control, n = 3; SMA, n = 3; MN-rescued SMA, n = 6; average of 44 MN per mouse). K, SMA mice had significantly fewer synapses juxtaposed to MNs per 100 μm of soma (2.74 ± 0.05, p = 0.04) relative to control littermates (3.67 ± 0.32). MN-rescued SMA mice were significantly improved relative to SMA mice (3.92 ± 0.19; p = 0.003; 1-way ANOVA, Bonferroni's post-test). Scale bars: 50 μm. Values are shown as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01.