The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction.
The Putative Drosophila TMEM184B Ortholog Tmep Ensures Proper Locomotion by Restraining Ectopic Firing at the Neuromuscular Junction.
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DOI：
10.1007/s12035-022-02760-3
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发表时间：
2022-04
影响因子：
5.1
通讯作者：
Bhattacharya, Martha R. C.
中科院分区：
文献类型：
--
作者：
Cho, Tiffany S.;Beigaite, Egle;Klein, Nathaniel E.;Sweeney, Sean T.;Bhattacharya, Martha R. C.
TMEM184 B是一种推定的七通道膜蛋白，其在损伤后促进轴突变性。TMEM184B突变导致小鼠神经肌肉结构异常以及感觉和运动行为缺陷。TMEM184B引起神经肌肉缺陷的机制尚不清楚。我们采用果蝇研究功能密切相关的基因，Tmep（CG12004），在神经肌肉接头。我们表明，TMEP是所需的充分成人的生存能力和有效的幼虫运动。与对照组相比，Tmep突变体幼虫的身体收缩率降低，雌性的缺陷更强。在来自体壁肌肉的记录中，Tmep突变体显示出显著的超兴奋性，其中许多突触后电位响应于单个刺激而被激发，这与Tmep在抑制突触兴奋性中的作用一致。Tmep突变神经肌肉接头处的额外分支和卫星结与活性依赖性突触过度生长一致。Tmep在运动神经元内的核内体和突触囊泡中表达，提示其可能在突触膜运输中起作用。使用RNAi敲低，我们表明，Tmep是必要的运动神经元适当的幼虫运动和兴奋性，它的减少增加突触前钙的水平。运动缺陷可以通过突触前敲低内质网钙通道或通过降低诱发释放概率来挽救，进一步表明过度的突触活动驱动行为缺陷。我们的工作确立了Tmep在调节突触传递和运动行为中的关键功能。
TMEM184B is a putative seven-pass membrane protein that promotes axon degeneration after injury. TMEM184B mutation causes aberrant neuromuscular architecture and sensory and motor behavioral defects in mice. The mechanism through which TMEM184B causes neuromuscular defects is unknown. We employed Drosophila melanogaster to investigate the function of the closely related gene, Tmep (CG12004), at the neuromuscular junction. We show that Tmep is required for full adult viability and efficient larval locomotion. Tmep mutant larvae have a reduced body contraction rate compared to controls, with stronger deficits in females. In recordings from body wall muscles, Tmep mutants show substantial hyperexcitability, with many post-synaptic potentials fired in response to a single stimulation, consistent with a role for Tmep in restraining synaptic excitability. Additional branches and satellite boutons at Tmep mutant neuromuscular junctions are consistent with an activity-dependent synaptic overgrowth. Tmep is expressed in endosomes and synaptic vesicles within motor neurons, suggesting a possible role in synaptic membrane trafficking. Using RNAi knockdown, we show that Tmep is required in motor neurons for proper larval locomotion and excitability, and that its reduction increases levels of presynaptic calcium. Locomotor defects can be rescued by presynaptic knock-down of endoplasmic reticulum calcium channels or by reducing evoked release probability, further suggesting that excess synaptic activity drives behavioral deficiencies. Our work establishes a critical function for Tmep in the regulation of synaptic transmission and locomotor behavior.
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