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
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DOI：
10.1073/pnas.1002176107
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发表时间：
2010-09-14
影响因子：
11.1
通讯作者：
Wong, Philip C.
中科院分区：
文献类型：
--
作者：
Chiang, Po-Min;Ling, Jonathan;Wong, Philip C.
达特激活调节DNA结合蛋白（Tardbp或TDP-43），一种高度保守的后生动物DNA/RNA结合蛋白，被认为参与RNA转录和剪接，已与肌萎缩侧索硬化症和额颞叶变性的病理生理学相关，并且对早期胚胎发育至关重要。然而，TDP-43在成人中的生理作用及其下游靶点都没有很好的定义。为了解决这些问题，我们开发了条件性Tardbp-KO小鼠和胚胎干（ES）细胞模型。在这里，我们表明，小鼠出生后Tardbp的缺失导致体内脂肪急剧减少，随后迅速死亡。此外，条件性Tardbp-KO ES细胞不能增殖。重要的是，对缺乏Tardbp的ES细胞的转录组的高通量DNA测序分析揭示了TDP-43的一组下游靶点。我们发现，Tbc 1d 1，一个已知介导瘦和肥胖的基因，在TDP-43的情况下下调。总的来说，我们的结果确定TDP-43对脂肪代谢和ES细胞存活至关重要。
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.