Mouse Genome Informatics
involves: FVB/N
phenotype observed in females
phenotype observed in males
N normal phenotype
• none survive past 4 months of age (J:22628)
• compensating the energetic imbalance with a highly energetic diet extends the mean survival by 20% and improves motor neuronal function (J:91800)

• cease food and water intake
• exhibit an age-related rapidly progressive decline of motor function
• animals show increased incidence of falling
• mice show reduced ability with aging to remain on rotating rod
• progressive decrease in grip strength is observed starting at around 15 weeks of age
• at 3-4 months of age, develop a generalized weakness that progresses within 72 hours to total immobility
• develop a spastic paralysis, initially involving the hindlimbs but progressing to the forelimb, that is associated with profound muscle wasting

nervous system
• neuron loss is also seen in the hypoglossal nucleus but it is more variable and much milder than the loss in the facial nucleus
• consistent neuronal loss in the oculomotor nucleus is seen only in the two most severely affected mice
• exhibit a variable (16-72%) decrease in neuron number in the facial nucleus and a smaller nuclear volume
• exhibit a moderate deletion of neurons in the trigeminal motor nucleus
• within the brain stem and neocortex, show degenerative changes in the motor components of cranial nerve nuclei
• exhibit a few dystrophic neurites in the dorsal horn, however do not detect any argyrophilic perikarya
• exhibit moderate to severe degenerative changes within the ventral horns
• exhibit numerous dystrophic neurites in the ventral horn gray matter, large and small argyrophilic perikarya, and swollen fragmented processes
• exhibit neurodegeneration of motorneurons within the spinal cord, brain stem, and neocortex and show some degenerative changes in the hypothalamus, deep layers of the superior colliculus, deep cerebellar nuclei, basal ganglia, and thalamus
• exhibit pronounced loss of large spinal motorneurons, with remaining motorneurons showing pyknosis and karyorrhexis
• exhibit degeneration of a few cortical motorneurons in layer V

• exhibit progressive muscle wasting
• exhibit skeletal muscle hypermetabolism as indicated by increased muscle expression of genes involved in lipid and carbohydrate metabolism

adipose tissue
• exhibit reduced adipose tissue accumulation
• seen in both asymptomatic and symptomatic homozygotes
• epididymal and retroperitoneal white adipose tissue is markedly reduced or almost nonexistent in the asymptomatic phase of the disease

• body mass and body weight is lower in symptomatic (75 days of age) and early symptomatic (105 days of age) mutants
• mice show decrease in body weight compared to controls from 14-16 weeks after birth onwards

• unable to maintain body temperature when placed under conditions in which adaptive thermogenesis is challenged; show lower rectal temperature than wild-type when fasted for 24 hours or exposed to 4 degrees C
• plasma leptin levels are diminished
• plasma T3 levels are decreased in older early symptomatic (105 days old) mutants
• exhibit increased energy expenditure at rest
• exhibit higher rates of total oxygen consumption
• respiratory quotient is lower
• fasted homozygotes clear glucose more efficiently than wild-type when injected with glucose
• fasted mutants incorporate a nonmetabolizable glucose analog in white adipose tissue and skeletal muscle
• exhibit a higher fasting glycemia than wild-type, although no differences are seen under normal feeding conditions
• levels of circulating ketone bodies, an indicator of fatty acid oxidation, increase with age
• norepinephrine-stimulated glycerol release is higher in white adipose tissue transplants than in wild-type, indicating an increase of activated lipolysis

Mouse Models of Human Disease
Amyotrophic Lateral Sclerosis 1; ALS1 105400 J:22628 , J:58733 , J:91800