title: Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis.
abstract: Abnormal TDP-43 aggregation is a prominent feature in the neuropathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in TARDBP, the gene encoding TDP-43, cause some cases of ALS. The normal function of TDP-43 remains incompletely understood. To better understand TDP-43 biology, we generated mutant mice carrying a genetrap disruption of Tardbp. Mice homozygous for loss of TDP-43 are not viable. TDP-43 deficient embryos die about day 7.5 of embryonic development thereby demonstrating that TDP-43 protein is essential for normal prenatal development and survival. However, heterozygous Tardbp mutant mice exhibit signs of motor disturbance and muscle weakness. Compared with wild type control littermates, Tardbp (+/-) animals have significantly decreased forelimb grip strength and display deficits in a standard inverted grid test despite no evidence of pathologic changes in motor neurons. Thus, TDP-43 is essential for viability, and mild reduction in TDP-43 function is sufficient to cause motor deficits without degeneration of motor neurons.
authors.affiliation: Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. kraemerb@u.washington.edu
authors.forename: Brian C
authors.initials: BC
authors.lastname: Kraemer
authors.forename: Theresa
authors.initials: T
authors.lastname: Schuck
authors.forename: Jeanna M
authors.initials: JM
authors.lastname: Wheeler
authors.forename: Linda C
authors.initials: LC
authors.lastname: Robinson
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology; D005552:Forelimb / Q000378:metabolism; D018737:Hand Strength; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000235:genetics*; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism*; D009154:Mutation
chemical_list: D004268:DNA-Binding Proteins