Figure 3. Restoration of the SMN protein in symptomatic SMA model mice rescues the disease phenotype.

(A) Western blotting reveals disease state levels of spinal cord SMN protein in nontreated P4 animals homozygous for the hybrid allele. (B) NMJ pathology in untreated P4 mutants manifests as poor terminal arborization and NF engorged nerve terminals (arrowheads). (C) Postsymptomatic TM treatment of Cre-ER–positive but not Cre-ER–negative mutant mice overcomes disease-related downturn in growth at P13 and accounts for a significant increase in weight by P17 (n ≥ 16, **P < 0.01, Student’s t test). (D) Improved motor performance in a righting reflex assay (n ≥ 4) following TM treatment at P4. (E) Mutant SMN2;Δ7;Cre-ER;Smn^Res/Res mice treated at P4 with TM and sacrificed at P16–P17 express increased SMN protein in nervous as well as nonnervous tissue. Controls were WT (Smn^+/+) at the murine Smn locus. (F) NMJs of gastrocnemius muscle of TM-treated mutants exhibit a reduction but not complete absence of pathology at P17 (solid arrowhead), whereas those of untreated mutants become progressively worse, displaying NF swollen nerve terminals (arrows) and immature, plaque-like motor endplates (open arrowheads). (G) Significant increase in the size of the motor endplate of TM-treated mutants compared with those of untreated mutants (100 endplates assessed in each of 3 mice; *P < 0.05; **P < 0.01, Student’s t test). (H) An increase in SMN-mediated snRNP assembly is observed in TM-treated mutants at 4 days after treatment. n = 4, *P < 0.05, Student’s t test. Scale bars: 10 μm (B); 40 μm and 10 μm (enlarged images of NMJs). (F). Data are represented as mean ± SEM.