Interestingly, a recent RNAi knockdown study revealed histone deacetylase 6 (HDAC6) as a target of TDP-43 in cultured cells ( 14).Īs TDP-43 is essential for early embryogenesis ( 15 – 17), we elected to develop a conditional Tardbp-KO mouse model to determine the physiological role of TDP-43 in the adult animal.
Moreover, because increased expression of TDP-43 is also toxic to motor neurons ( 12, 13), it will be also important to identify a set of downstream targets of TDP-43 to facilitate our understanding of pathways that may be impacted by TDP-43. 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. 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). Interestingly, most of these mutations identified to date are localized to the C-terminal domain of TDP-43, a heterogeneous nuclear ribonucleoprotein–interacting region that may be critical for the normal function of the protein.
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. 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). Biophysical studies indicate that TDP-43 forms a dimer harboring two RNA-binding domains that preferentially bind to TG/UG repeats ( 5). Identified 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). Collectively, our results establish that TDP-43 is critical for fat metabolism and ES cell survival. We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. Importantly, high-throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. Moreover, conditional Tardbp-KO ES cells failed to proliferate. Here, we show that postnatal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death. To address these questions, we developed conditional Tardbp-KO mice and embryonic stem (ES) cell models. However, neither the physiological role of TDP-43 in the adult nor its downstream targets are well defined. 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.