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

Kraemer, Brian C.; Schuck, Theresa; Wheeler, Jeanna M.; Robinson, Linda C.; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Schellenberg, Gerard D.

doi:10.1007/s00401-010-0659-0

Cited by 304 publications

(263 citation statements)

References 54 publications

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“…S1), suggesting that the level of TDP-43 is tightly controlled and compensated in the Tardbp +/− mice. However, no live-born Tardbp −/− mice were identified from ten intercrosses of Tardbp +/− mice (number of pups obtained: control/Tardbp +/− / Tardbp −/− , 23/37/0), confirming that Tardbp is essential for embryogenesis (15)(16)(17). Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.…”

Section: Resultsmentioning

confidence: 95%

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Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Chiang

Ling

Jeong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

265

250

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Tat activating regulatory DNA-binding protein (Tardbp or TDP-43), a highly conserved metazoan DNA/RNA binding protein thought to be involved in RNA transcription and splicing, has been linked to the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration and is essential for early embryonic development. However, neither the physiological role of TDP-43 in the adult nor its downstream targets are well defined. To address these questions, we developed conditional Tardbp-KO mice and embryonic stem (ES) cell models. Here, we show that postnatal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death. Moreover, conditional Tardbp-KO ES cells failed to proliferate. Importantly, high-throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. Collectively, our results establish that TDP-43 is critical for fat metabolism and ES cell survival.conditional knockout mice | amyotrophic lateral sclerosis | frontotemporal dementia | energy metabolism | RNA-sequencing I dentified initially as a cellular protein that regulates human immunodeficiency viral gene transcription (1), Tat activating regulatory DNA-binding protein (Tardbp or TDP-43) is a highly conserved DNA/RNA-binding protein thought to regulate alternative splicing of cystic fibrosis transmembrane conductance regulator (CFTR) and survival of motor neuron (SMN) through binding to heterogeneous nuclear ribonucleoprotein or (UG) n repeats of these target transcripts (2-4). Biophysical studies indicate that TDP-43 forms a dimer harboring two RNA-binding domains that preferentially bind to TG/UG repeats (5). Whereas TDP-43 is normally localized to the nucleus, it is redistributed as insoluble aggregates in neuronal nuclei, perikarya and neurites in amyotrophic lateral sclerosis (ALS) (6, 7) and frontotemporal lobar degeneration (FTLD) (8). The identification of missense mutations in TARDBP in familial and sporadic ALS (9, 10) supports the idea that this nuclear protein plays a critical role in the pathogenesis of these neurodegenerative disorders. Interestingly, most of these mutations identified to date are localized to the Cterminal domain of TDP-43, a heterogeneous nuclear ribonucleoprotein-interacting region that may be critical for the normal function of the protein. Although mutant TDP-43 mice showed evidence of neurodegeneration, no TDP-43-positive cytoplasmic aggregates were observed in neurons of these mutant mice, suggesting that altered RNA metabolism rather than TDP-43 aggregates underlies the pathogenesis of ALS or FTLD (11).To begin clarifying the molecular basis of mutant TDP-43-linked disease, it will be crucial to understand the physiological and cellular functions of TDP-43. Moreover, because increased expression of TDP-43 is also toxic to motor neurons (12, 13), it will be also important to identify a set ...

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Section: Resultsmentioning

confidence: 95%

“…As TDP-43 is essential for early embryogenesis (15)(16)(17), we elected to develop a conditional Tardbp-KO mouse model to determine the physiological role of TDP-43 in the adult animal. We now show that TDP-43 is critical for fat storage in the adipocytes.…”

mentioning

confidence: 99%

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Chiang

Ling

Jeong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

265

250

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“…Animals were tested and weighed every 3-4 d. The grid test was a binary modification of a described test (39). Briefly, each mouse was placed onto a metal grid, which was positioned ≈30 cm above a soft surface.…”

Section: Methodsmentioning

confidence: 99%

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Marinković

Reuter

Brill

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Axonal transport deficits have been reported in many neurodegenerative conditions and are widely assumed to be an immediate causative step of axon and synapse loss. By imaging changes in axonal morphology and organelle transport over time in several animal models of amyotrophic lateral sclerosis (ALS), we now find that deficits in axonal transport of organelles (mitochondria, endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (i) Axons can survive despite long-lasting transport deficits: In the SOD G93A model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (ii) Transport deficits are not necessary for axon degeneration: In the SOD G85R model of ALS, motor axons degenerate, but transport is unaffected. (iii) Axon transport deficits are not sufficient to cause immediate degeneration: In mice that overexpress wild-type superoxide dismutase-1 (SOD WT ), axons show chronic transport deficits, but survive. These data suggest that disturbances of organelle transport are not a necessary step in the emergence of motor neuron degeneration.

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“…Thus, the main approach to studying LOF, by using null mice, has been hampered because TDP‐43 knockout (KO) causes very early embryonic lethality, and heterozygous mice have normal levels of TDP‐43 due to autoregulation (Kraemer et al , 2010; Sephton et al , 2010; Wu et al , 2010; Ricketts et al , 2014). However, conditional KO strategies and downregulation of TDP‐43 via siRNA suggest that acute TDP‐43 loss of function could lead to neurodegeneration (Chiang et al , 2010; Wu et al , 2012; Iguchi et al , 2013; Yang et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

et al. 2018

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TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

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

Cited by 304 publications

References 54 publications

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Axonal transport deficits and degeneration can evolve independently in mouse models of amyotrophic lateral sclerosis

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

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