Reduced brain and body weight and motor dysfunction in TDP-43
mice. (A-B) Upon tail elevation, NT mice (A) showed normal escape response by splaying their hind limbs while homozygous TDP-43M337V mice (B) held their hind limbs close to their body and failed to show proper escape extension. (C-D) Gait of NT and TDP-43M337V mice was evaluated by inked foot placement on paper. 1 month old (C) NT mice show normal foot placement and gait; whereas, (D) homozygous TDP-43M337V mice showed an irregular, inwardly-placed foot falls with a dragging pattern. Forepaws and hind paws were coated in red and blue ink, respectively, to evaluate placement of paws during travel. (E) At 1 month, brain weight and (F) body weight of homozygous TDP-43M337V mice was significantly lower than that of age-matched NT and hemizygous mice. Brain weight: NT = 428 ± 9 mg; Hemi = 429 ± 11 mg; Homo = 338 ± 29 mg. Body weight: NT = 12.3 ± 1 g; Hemi = 12 ± 2 g; Homo = 6 ± 2 g. Data shown are the means ± SEM of 6-8 mice per group. ***p < 0.0001. (G) Hemizygous TDP-43M337V mice were mated, and the survival of the resulting pups of each genotype was determined. The results are plotted as a percentage of pups alive per postnatal day of life. Survival rate for all cohorts were calculated using Kaplan-Meier methods (p < 0.001 for overall log-rank test). Homozygous TDP-43M337V mice had higher mortality (about 70% death) around 1 month of age, which was statistically significant compared with NT and hemizygous littermates (p < 0.001).