Inhibition of ERK pathway by U0126 induces a significant motor neuron protection, increases lifespan, and improves weight curve in severe SMA-like mice. A–G, Immunodetection of ChAT-positive motor neurons in the lumbar spinal cord (L1–L5) of vehicle-treated (A) and U0126-treated control (B) mice at 2 d of age, vehicle-treated (C) and U0126-treated control (D) mice at 6 d of age, vehicle-treated (E) and U0126-treated SMA-like mice at 2 d of age (F), and U0126-treated SMA-like mice at 6 d of age (G). Scale bars, 100 μm. H–J, Quantitative analysis of the number (H) and the cell body area (I, J) of motor neurons per ventral horn in the ventral lumbar spinal cord of vehicle- and U0126-treated control mice at 2 and 6 d of age, vehicle-treated SMA-like mice at 2 d of age, and vehicle- and U0126-treated SMA-like mice at 6 d of age (n = 4). K, Lifespan of U0126-treated SMA-like mice (n = 22) compared with vehicle-treated (n = 12) and untreated SMA-like mice (n = 10). L, Weight curve in U0126-treated (n = 22) and vehicle-treated SMA-like mice (n = 12) compared with U0126-treated (n = 15) and vehicle-treated control (n = 15) mice. M, Time spent to stand up after being placed on the side for vehicle-treated (n = 5) and U0126-treated control (n = 5) mice compared with vehicle-treated (n = 5) and U0126-treated SMA-like mice (n = 5). N, O, Total number of crossings (N) and mobility (O) during 5 min in the open-field test for vehicle-treated (n = 5) and U0126-treated control (n = 5) mice compared with vehicle-treated (n = 5) and U0126-treated SMA-like (n = 5) mice. Data are displayed as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.