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Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis

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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.

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Acknowledgments

This work was supported by NIH grant AG17586 to GDS, VMYL, and JQT. This work was also supported by grants to BCK from the Office of Research and Development Medical Research Service, Department of Veterans Affairs and NIH (NS064131). This work utilized facilities at the VA Puget Sound Health Care System, Seattle, Washington. We thank Eddie Lee for outstanding assistance examining neuropathology of Tardbp+/− animals and Elaine Loomis, Leojean Anderson, and Harmony Danner for excellent technical assistance. The lacZ monoclonal antibody was obtained from the Developmental Studies Hybridoma Bank maintained by the University of Iowa.

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Authors and Affiliations

  1. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA

    Brian C. Kraemer, Jeanna M. Wheeler & Linda C. Robinson

  2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104, USA

    Brian C. Kraemer & Jeanna M. Wheeler

  3. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-6100, USA

    Theresa Schuck, John Q. Trojanowski, Virginia M. Y. Lee & Gerard D. Schellenberg

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  1. Brian C. Kraemer
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Correspondence to Brian C. Kraemer.

Electronic supplementary material

401_2010_659_MOESM1_ESM.tif

Fig. S1 Analysis of genetrap targeted TDP-43 locus. Southern blotting was conducted as described (35) using random primed TDP-43 exon 1 and beta-geo coding sequence specific 32P-labeled probes and conditions as described for northern blotting. 20 micrograms of genomic DNA isolated from liver was digested with AflIII and PstI for TDP-43 and beta-geo specific probes respectively. Bands of ~3.6 kb corresponding to no genetrap and ~4.5 kb corresponding to a genetrap insertion in the TDP-43 locus were observed for the TDP-43 exon 1 probe. A single genetrap specific band was observed for the exon 1 probe corresponding to the 7.5 kb beta-geo containing genetrap inserted within the TDP-43 locus (TIFF 5,547 kb)

401_2010_659_MOESM2_ESM.tif

Fig. S2 Analysis of amino and carboxy terminal TDP-43 specific fragments inTardbp +/−mice. Immunoblotting of brain, heart, kidney, liver, lung, muscle, and spleentissue protein extracts. Duplicate blots were probed with a. N-terminal TDP-43 specificantibody. b. C-terminal specific TDP-43 antibody (TIFF 11,345 kb)

401_2010_659_MOESM3_ESM.tif

Fig. S3 Young Tardbp +/− animals do not display deficits in grip strength.a. Thirty day oldTardbp +/− animals (n = 16) hung on an inverted wire grid for the same lengthof time as control animals (n = 23) and b. also exhibit similar maximum forelimb gripstrength. Individual scores are the average of three trials, and the error bars representstandard deviation (TIFF 9,928 kb)

401_2010_659_MOESM4_ESM.tif

Fig. S4 Aged Tardbp +/− spinal cord is similar to wild type littermates.Shown here are images of sacral spinal cord of 28 month old mice. a. Tardbp +/+ and b.Tardbp +/− . As described in the text, there are no differences in cord these tissues betweenTardbp +/− and wild type mice. The bar in each panel = 100 um (TIFF 53,387 kb)

401_2010_659_MOESM5_ESM.tif

Fig. S5 Aged Tardbp +/− muscle is similar to wild type littermates.Shown here are images of gastronemius muscle of 28 month old mice. a. Tardbp +/+ and b.Tardbp +/−. As described in the text, there are no differences in cord these tissues betweenthe Tardbp +/− and wild type mice. The bar in each panel = 100 um (TIFF 53,517 kb)

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Kraemer, B.C., Schuck, T., Wheeler, J.M. et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119, 409–419 (2010). https://doi.org/10.1007/s00401-010-0659-0

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