Phenotypes Associated with This Genotype

Genotype
MGI:5695547

• Allelic Composition: Tg(NEFH-tTA)8Vle/0; Tg(tetO-TARDBP*)4Vle/0
• Genetic Background: involves: C3H/HeJ * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

nervous system

decreased brain size ( J:225639 )

• significantly smaller brains are observed 8-10 weeks following Dox removal

thin cerebral cortex ( J:225639 )

• decreased cortical thickness beginning at 4 weeks following Dox removal

brain atrophy ( J:225639 )

• brain atrophy is observed following Dox removal

astrocytosis ( J:225639 )

• astrogliosis is observed 4 weeks after Dox removal

abnormal innervation pattern to muscle ( J:225639 )

• denervation of neuromuscular junctions (NMJ) beginning 4 weeks after Dox removal

• by 6 weeks only 39.6% of NMJs are intact in tibialis anterior

abnormal neuron morphology ( J:225639 )

• loss of endogenous nuclear mouse TARDBP+ 2-4 weeks following Dox removal

• accumulation of cytoplasmic ubiquitin with TARDBP+ inclusions occurs in brains and spinal cord

decreased motor neuron number ( J:225639 )

• 28% loss of lumbar motor neurons by 6 weeks following Dox removal; 50% loss by 8 weeks

abnormal neuromuscular synapse morphology ( J:225639 )

• denervation of neuromuscular junctions (NMJ) beginning 4 weeks after Dox removal

• by 6 weeks only 39.6% of NMJs are intact in tibialis anterior

neuronal cytoplasmic inclusions ( J:225639 )

• accumulation of insoluble, phosphorylated cytoplasmic TARDBP+ inclusions in brain and spinal cord is detected as early as 1 week following Dox removal and reaches high levels by 4 weeks

• accumulation of insoluble TARDBP occurs prior to phosphorylation of protein

• inclusions are detected in motor cortex, striatum, visual and entorhinal, and somatosensory cortex, cerebellum and hippocampus

• inclusions are detected in fewer than 2% of spinal cord neurons

• by disease end stage 28% of neurons contain TARDBP+ puncta

neurodegeneration ( J:225639 )

behavior/neurological

limb grasping ( J:225639 )

• hindlimb clasping following Dox removal

tremors ( J:225639 )

• forelimb and/or hindlimb tremor following Dox removal

impaired balance ( J:225639 )

• progressive decline in balance as measured by accelerating rotarod occurs beginning 2 weeks after Dox removal

impaired coordination ( J:225639 )

• progressive decline in coordinated movement as measured by accelerating rotarod occurs beginning 2 weeks after Dox removal

decreased grip strength ( J:225639 )

• progressive loss of grip strength as measured by wire hang test occurs beginning 2 weeks after Dox removal

mortality/aging

premature death ( J:225639 )

• mice die 10-18 weeks after removal of Dox; lifespan is extended if Dox is re-introduced

• median survival is 10.3 weeks off Dox

muscle

decreased skeletal muscle mass ( J:225639 )

• decrease in mass of isolated tibialis anterior and gastrocnemius muscles following Dox removal

growth/size/body

weight loss ( J:225639 )

• progressive weight loss beginning 2 weeks after Dox removal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
amyotrophic lateral sclerosis type 10		DOID:0060201	OMIM:612069	J:225639