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1.
Figure 5

Figure 5. Accumulation of ubiquitin in mutant FUS transgenic rats.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A–L) Double-fluorescence staining revealed accumulation of ubiquitin in the cortex (D–F) and spinal cord (J–L) of the mutant FUS transgenic rats (line 16) at paralysis stages, but not in tissues of the age-matched normal FUS transgenic rats (line 20) (A–C: cortex; G–I: spinal cord). Coronal sections of the frontal cortex and traverse sections of the lumbar cord were immunostained with antibodies to ubiquitin (green) and human FUS (red). Scale bars: A–F, 20 µm.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.
2.
Figure 6

Figure 6. Proliferation of astrocytes and microglia in mutant FUS transgenic rats.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A–K) Immunofluorescence staining for the microglia marker Iba-1 (A–F) and the astrocyte marker GFAP (H–K) in the mutant FUS transgenic rats of line 16 at the paralysis stage (R521C) and in their nontransgenic age-matched littermates (NT). Coronal sections of the frontal cortex and traverse sections of the lumbar spinal cord were immunostained with antibodies to Iba-1 (red) or GFAP (green). Scale bars: 100 µm.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.
3.
Figure 3

Figure 3. Loss of neurons in the cortex and hippocampus of mutant FUS transgenic rats.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A–C) Cresyl violet staining of hippocampus (A–B and E–F) and cortex (C–D and G–H) showed faint staining in the tissues of mutant FUS transgenic rats at disease end-stages (B, D, F, and H) compared to age-matched nontransgenic rats (A, C, E, and G). Scale bars: A–B, 400 µm; C–D, 50 µm; and E–H, 20 µm. (I, J) Stereological cell counting revealed a loss of neurons in the cortex (I) and dentate gyrus (J) of mutant FUS transgenic rats (lines 16 and 20). The CAG-tTA single transgenic rats and nontransgenic rats were combined as control rats (NT) because no difference was observed between these rats. Mutant FUS transgenic rats were killed at disease end-stages and paired control rats were killed at matched ages. Normal FUS transgenic rats and their paired controls were killed at 70 days of age, by which time mutant FUS transgenic rats had reached disease end-stages. Data are presented as means ± SD (n = 5–7). *p<0.05.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.
4.
Figure 4

Figure 4. Neuron loss accompanied by ubiquitin aggregation in aged rats overexpressing the normal human fus gene.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A–C) Double-fluorescence staining for human FUS (A, red) and the neuronal marker NeuN (B, green) in the frontal cortex of normal human FUS transgenic rats (line 20). Most FUS-positive cells expressed NeuN, but some did not (C). (D–I) Immunofluorescence staining revealed ubiquitin aggregation in aged (G–I; 1 year of age), but not young (D–F; 3 months of age), normal FUS transgenic rats. Coronal sections of frontal cortex were immunostained with antibodies to ubiquitin (D, G: green) and human FUS (E, H: red). Scale bars: A–C, 100 µm; D–I, 20 µm. (J, K) Barnes maze analysis revealed spatial learning deficits in normal FUS transgenic rats of line 20 at advanced ages. One year old transgenic rats (TG) and their nontransgenic littermates (NT) were tested in a Barnes maze and time spent to locate the fixed escape hole (latency) and the number of errors made before escaping were recorded. (L, M) Stereological cell counting revealed a loss of neurons in the cortex (J) and dentate gyrus (K) of normal FUS transgenic rats at advanced ages (line 20). Coronal sections of one hemisphere were stained with Cresyl violet and the number of neurons in the frontal cortex and dentate gyrus was estimated by stereological cell counting. Normal FUS transgenic rats and their nontransgenic controls were killed at the age of 1 year. Data are presented as means ± SD (n = 5). * p<0.05.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.
5.
Figure 1

Figure 1. Progressive paralysis in transgenic rats overexpressing a mutant human FUS.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A) Immunoblotting showed expression of human FUS in normal (WT) and mutant (R521) fus transgenic rats, but not in nontransgenic controls (NT). Each lane was loaded with 30 µg of total protein in the lysates of spinal cord. The blotting membrane was probed with an antibody to human FUS (made in-house) and then with an antibody against GAPDH after stripping. The number of transgenic lines corresponds to the number of FUS transgene copies. * indicates a non-specific band. (B–F) Immunohistochemistry detected expression of human FUS in the cortex (B) and spinal cord (D, E) of FUS transgenic rats (line 16), but not in tissues of nontransgenic littermates (C, cortex; F, spinal cord). Expression of human FUS in lumbar spinal cord profiled at a low magnification (D). Human FUS was diffusely located in the cytoplasm of motor neurons in the ventral horn (E). Scale bars: B–C and E–F: 20 µm; D, 100 µm. (G, H) Representative photographs of male transgenic rats of line 22 (G, 30 days of age) and line 16 (H, 60 days of age) at paralysis stages. (I, J) Graphs show the probability of disease onset (I) and survival (J) in FUS transgenic rats. Disease onset was defined as an unrecoverable reduction in the grip strength of fore or hind paws. Rats were euthanized and counted as dead when two or more legs were paralyzed or body weight was reduced by 30%. All FUS transgenic rats carried the CAG-tTA transgene. Breeding female rats were given Dox in their drinking water (50 µg/ml) until delivery. Each group contained 13 to 16 rats.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.
6.
Figure 2

Figure 2. Motor neuron degeneration accompanied by denervation atrophy of skeletal muscle.. From: FUS Transgenic Rats Develop the Phenotypes of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration.

(A–C) Cresyl violet staining of motor neurons in the L3 ventral horn of mutant FUS transgenic (C, line 16), age-matched nontransgenic (A), and normal FUS transgenic (B, line 20) rats. (D, E) Bielschowsky silver staining detected degenerating neurons (arrows) in the spinal cord of mutant FUS transgenic rats at paralysis stages (E, line 16), but not in that of age-matched normal FUS transgenic rats (D, line 20). Note that degenerating neurons were rare in the mutant FUS transgenic rats even at paralysis stages. (F–K) Toluidine blue staining of axons of the dorsal corticospinal tract (F, G), L3 ventral roots (H, I), and L3 dorsal roots (J, K). Degenerating axons were seen in paralyzed mutant FUS transgenic rats of line 16 (G, I, K), but not in age-matched normal FUS transgenic rats of line 20 (F, G, J). (L, M) Electron microscopy of the motor axons in the L3 ventral roots of paralyzed mutant FUS (M, line 16) and age-matched normal FUS transgenic rats (L, line 20). Arrows point to degenerating axons. (N, O) H&E staining showed group atrophy (arrows) of the gastrocnemius muscle in paralyzed mutant FUS (O), but not in age-matched normal FUS (N) transgenic rats. (P) Electromyography of gastrocnemius muscles revealed fibrillation (arrows) and fasciculation (arrow head) potentials in a mutant FUS transgenic rat (R521C), but not in its nontransgenic littermate (NT). (Q) Confocal microscopy of the focal structures of neuromuscular junctions (NMJ) in gastrocnemius muscles. Compared to the NMJ of a nontransgenic littermate (NT), the NMJ of a mutant FUS transgenic rat (R521C) was denervated. While axon terminals were visualized by immunostaining for synaptophysin (SYN) and neurofilament (NF), postsynaptic nicotinic receptors were visualized with Alexa fluor 555-conjugated α-bungarotoxin (α-BTX). (R) Quantification of NMJ revealed a reduction of intact NMJ in the mutant FUS (lines 16 and 22), but not in the normal FUS (line 20), transgenic rats. Twenty NMJs were examined for each animal (5-6 rats per genotype). *p<0.05, transgenic rats vs. nontransgenic rats. (S) Stereological cell counting revealed the number of large neurons (>25 µm in diameter) in the ventral horn of L3 spinal segments taken from nontransgenic (NT) or transgenic (TG) rats. Data are presented as means ± SD (n = 9–11). Scale bars: A–E, 50 µm; F–K, 20 µm; L, M, 5 µm; N, O, 30 µm.

Cao Huang, et al. PLoS Genet. 2011 March;7(3):e1002011.

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