Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans.
Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans.
复制标题
RAP2和TNIK控制丛蛋白依赖性瓷砖秀丽隐杆线虫中的突触神经。
DOI：
10.7554/elife.38801
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发表时间：
2018-07-31
期刊：
影响因子：
7.7
通讯作者：
Mizumoto K
中科院分区：
文献类型：
--
作者：
Chen X;Shibata AC;Hendi A;Kurashina M;Fortes E;Weilinger NL;MacVicar BA;Murakoshi H;Mizumoto K
在发育过程中，神经元与它们命运决定的目标形成突触。虽然我们开始阐明细胞外配体-受体相互作用通过抑制突触发生来增强突触特异性的机制，但我们对其细胞内机制的了解仍然有限。在线虫中，Rap2 GTPase （rap-2）及其效应物TNIK （mig-15）在Plexin （plx-1）的下游发挥遗传作用，限制突触前组装并形成平铺突触神经。与plx-1突变体一样，构成型GTP和gdp形式的rap-2突变体都表现出突触平铺缺陷，这表明rap-2核苷酸状态的循环对突触抑制至关重要。一致地，PLX-1抑制局部RAP-2活性。在mig-15突变体中过多的异位突触形成导致严重的突触平铺缺陷。相反，过表达的米格-15强烈抑制突触的形成，表明米格-15是突触形成的负调节因子。这些结果表明，在体内，丛蛋白对小GTPase活性的亚细胞调控形成了适当的突触模式。基因不仅仅是决定我们头发或眼睛的颜色。它们产生的蛋白质几乎参与了身体的每一个过程。在人类中，大多数活性基因都在大脑中，它们帮助大脑发育和正常工作——有效地控制我们的行动和行为。大脑的功能单元，即神经细胞或神经元，通过在它们之间的间隙，即突触中释放信使分子来相互交流。然后，这些分子从接收神经元的特定受体蛋白中被拾取。在神经系统中，神经元只与它们需要连接的细胞形成突触，即使它们周围有更多的细胞。这意味着它们使用特定的机制来阻止神经元与不正确的靶细胞形成突触。这一点很重要，因为如果存在太多的突触，或者如果突触与错误的目标细胞形成，就会损害神经系统的信息流。这最终会导致各种神经系统疾病，包括自闭症谱系障碍。2013年，研究人员发现，在秀丽隐杆线虫（Caenorhabditis elegans）中，一种名为丛蛋白（Plexin）的受体蛋白位于神经元表面，可以抑制附近突触的形成。现在，Chen等人——包括参与先前研究的一位作者——想要找出Plexin在阻止突触生长时操纵了哪些基因。了解这些基因的作用可以帮助我们理解神经元如何抑制突触。结果表明，Plexin可能调控Rap2和TNIK两个基因。Plexin降低了释放信使的神经元中Rap2的活性，从而阻碍了突触的形成。另一方面，基因TNIK和它的蛋白质具有修饰其他蛋白质的能力，因此可以抑制突触的生长。当TNIK在实验中被去除时，突触数量增加，但当其活性增加时，突触数量强烈减少。这些发现可以帮助科学家了解Rap2或TNIK的突变如何导致各种神经系统疾病。下一步将是测试这些基因是否也会影响其他物种（如老鼠）突触的形成。老鼠拥有更复杂的神经系统，在结构和功能上与人类更相似。
During development, neurons form synapses with their fate-determined targets. While we begin to elucidate the mechanisms by which extracellular ligand-receptor interactions enhance synapse specificity by inhibiting synaptogenesis, our knowledge about their intracellular mechanisms remains limited. Here we show that Rap2 GTPase (rap-2) and its effector, TNIK (mig-15), act genetically downstream of Plexin (plx-1) to restrict presynaptic assembly and to form tiled synaptic innervation in C. elegans. Both constitutively GTP- and GDP-forms of rap-2 mutants exhibit synaptic tiling defects as plx-1 mutants, suggesting that cycling of the RAP-2 nucleotide state is critical for synapse inhibition. Consistently, PLX-1 suppresses local RAP-2 activity. Excessive ectopic synapse formation in mig-15 mutants causes a severe synaptic tiling defect. Conversely, overexpression of mig-15 strongly inhibited synapse formation, suggesting that mig-15 is a negative regulator of synapse formation. These results reveal that subcellular regulation of small GTPase activity by Plexin shapes proper synapse patterning in vivo. Genes do more than just direct the color of our hair or eyes. They produce proteins that are involved in almost every process in the body. In humans, the majority of active genes can be found in the brain, where they help it to develop and work properly – effectively controlling how we move and behave. The brain’s functional units, the nerve cells or neurons, communicate with each other by releasing messenger molecules in the gap between them, the synapse. These molecules are then picked up from specific receptor proteins of the receiving neuron. In the nervous system, neurons only form synapses with the cells they need to connect with, even though they are surrounded by many more cells. This implies that they use specific mechanisms to stop neurons from forming synapses with incorrect target cells. This is important, because if too many synapses were present or if synapses formed with incorrect target cells, it would compromise the information flow in the nervous system. This would ultimately lead to various neurological conditions, including Autism Spectrum Disorder. In 2013, researchers found that in the roundworm Caenorhabditis elegans, a receptor protein called Plexin, is located at the surface of the neurons and can inhibit the formation of nearby synapses. Now, Chen et al. – including one author involved in the previous research – wanted to find out what genes Plexin manipulates when it stops synapses from growing. Knowing what each of those genes does can help us understand how neurons can inhibit synapses. The results revealed that Plexin appears to regulate two genes, Rap2 and TNIK. Plexin reduced the activity of Rap2 in the neuron that released the messenger, which hindered the formation of synapses. The gene TNIK and its protein on the other hand, have the ability to modify other proteins and could so inhibit the growth of synapses. When TNIK was experimentally removed, the number of synapses increased, but when its activity was increased, the number of synapses was strongly reduced. These findings could help scientists understand how mutations in Rap2 or TNIK can lead to various neurological conditions. A next step will be to test if these genes also affect the formation of synapses in other species such as mice, which have a more complex nervous system that is structurally and functionally more similar to that of humans.