Diet and energy-sensing inputs affect TorC1-mediated axon misrouting but not TorC2-directed synapse growth in a Drosophila model of tuberous sclerosis.
Diet and energy-sensing inputs affect TorC1-mediated axon misrouting but not TorC2-directed synapse growth in a Drosophila model of tuberous sclerosis.
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DOI：
10.1371/journal.pone.0030722
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Selleck SB
中科院分区：
文献类型：
--
作者：
Dimitroff B;Howe K;Watson A;Campion B;Lee HG;Zhao N;O'Connor MB;Neufeld TP;Selleck SB
雷帕霉素靶标（TOR）生长调节系统受许多不同输入的影响，包括生长因子信号传导、营养物质可用性和细胞能量水平。虽然TOR对细胞和生物体生长的影响已经得到了很好的表征，但这种途径对神经发育和行为也有深远的影响。上游TOR抑制剂TSC 1（结节性硬化症复合物1）或TSC 2的突变引起的TOR通路的过度激活会促进良性肿瘤和神经和行为缺陷，这是一种称为结节性硬化症（TS）的综合征。在果蝇中，神经元特异性过表达的Rheb，Tsc 1/Tsc 2抑制的直接下游目标，产生显着的突触过度生长，轴突路由错误，和趋光性缺陷。为了了解Tor信号的失调如何影响神经和行为发育，我们研究了生长因子，营养和能量感知输入对这些神经发育表型的影响。神经表达的Pi 3 K，生长因子输入Tor的主要介质，引起类似于Rheb的突触过度生长，但没有破坏轴突的指导或趋光性。饮食限制挽救了Rheb介导的行为和轴突导向缺陷，AMPK（细胞能量感应途径的一个组成部分）的过表达也是如此，但两者都不能挽救突触过度生长。虽然轴突引导和行为表型受到Tor复合体1（TorC 1）组件、Raptor或TORC 1下游元件（S6 k）功能改变的影响，但突触过度生长仅通过降低Tor复合体2（TorC 2）组件（Rictor，Sin 1）的功能来抑制。这些发现表明，Tor信号的不同输入在神经系统发育中具有不同的活动，Tor在营养能量感知系统和神经系统模式之间提供了重要的联系。
The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system.
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