TDP‐43, a neuro‐pathosignature factor, is essential for early mouse embryogenesis

Wu, Lien-Szu; Cheng, Wei-Cheng; Hou, Shin-Chen; Yan, Yu-Ting; Jiang, Shinn‐Jong; Shen, Che Kun James

doi:10.1002/dvg.20584

Cited by 238 publications

(186 citation statements)

References 24 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: 97%

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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.

264

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: 97%

“…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.

264

250

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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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“…Disruption in mice of the highly conserved Tardbp gene is embryonically lethal (19)(20)(21)(22). Similarly, postnatal inactivation of Tardbp (by Cre recombinase-mediated gene excision encoded by a ubiquitously-expressed CAG-Cre transgene) results in rapid postnatal death accompanied by defects in fat metabolism (22).…”

mentioning

confidence: 99%

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

Arnold

Ling

Huelga

et al. 2013

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

407

419

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Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43 Q331K and TDP-43 M337V ), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell typeselective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43 Q331K , but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43 Q331K enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.A myotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are progressive, adult-onset neurodegenerative diseases with overlapping clinical and pathological features (1-3). ALS is characterized by the selective loss of upper and lower motor neurons, leading to progressive fatal paralysis and muscle atrophy. A large majority (∼90%) of ALS and FTLD-U cases are without a known genetic cause. Importantly, in these sporadic cases, the appearance of ubiquitinated inclusions within the affected neurons of the nervous system characterizes both ALS and FTLD-U patients, suggesting an overlapping mechanism underlying both diseases. Biochemical characterization of brains and spinal cords from ALS and FTLD-U patients identified transactivating response region (TAR) DNA binding protein (TDP-43) as the major protein component of these ubiquitinated inclusions (4, 5). The discovery of ALS-linked mutations in the glycine-rich C-terminal domain of TDP-43 (6-8) demonstrated a pathological role of TDP-43 in both diseases. The subsequent identification of mutations in a structurally and functionally related nucleic acid binding protein, FUS/ TLS (fused in sarcoma/translocated in liposarcoma) (9, 10), further implicated defects in RNA processing in ALS pathogenesis.TDP-43 is a multifunctional nucleic acid binding protein.Within the nervous system, TDP-43 binds to >6,000 pre-mRNAs and affects the levels of ∼600 mRNAs and the splicing patterns of another 950 (11). Structura...

show abstract

TDP‐43, a neuro‐pathosignature factor, is essential for early mouse embryogenesis

Cited by 238 publications

References 24 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

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

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

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