Voltage-gated sodium channel scn8a is required for innervation and regeneration of amputated adult zebrafish fins.
Voltage-gated sodium channel scn8a is required for innervation and regeneration of amputated adult zebrafish fins.
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电压门控钠通道scn8a对成年斑马鱼断肢鳍神经支配和再生的作用。
DOI：
10.1073/pnas.2200342119
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发表时间：
2022-07-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
创伤中神经的存在是附件再生的一个重要组成部分。神经的再生效果是通过一定数量的神经末梢来实现的；然而，这种现象背后的分子机制在很大程度上仍不清楚。在这里，我们使用正向遗传筛选来鉴定一个突变体，该突变体表现出两个看似无关的温度敏感缺陷：运动和截肢鳍的再生。一个致病基因被定义为scn8ab，它编码神经元电压门控钠通道Nav1.6。在再生的早期阶段，scn8ab的突变会导致轴突再生和构型的中断，导致神经支配不足和再生障碍。这项研究揭示了损伤的附件中神经支配的一个关键因素，并为Nav1.6的功能提供了一个视角。硬骨鱼和尾龙两栖动物可以再生被切断的附肢，而这种能力仅限于成年哺乳动物的指尖。附件再生的一个重要组成部分是创面神经的再支配。然而，在成年脊椎动物受损的附属物中，神经支配是如何调节的，这方面的研究关注有限。从斑马鱼鳍再生中温度敏感缺陷的正向遗传学筛查中，我们发现了一种突变，该突变扰乱了再生，同时也导致了在限制性温度下的瘫痪。遗传图谱和互补测试确定了主要神经元电压门控钠通道(VGSC)基因scn8ab的突变。有条件地破坏scn8ab会损害早期的再生事件，包括胚泡的形成，但不影响已建立的再生体的形态发生。虽然scn8ab突变如预期那样降低了神经活性，但它们也扰乱了轴突再生和鳍再生中的模式，导致神经发育不足。我们的发现表明，VGSCs的活动通过促进附肢残端的神经支配而起到促进再生的作用。
A critical component for appendage regeneration is the presence of nerves in the wound. The regenerative effect of nerves is achieved by a threshold amount of nerve endings; however, the molecular mechanism underlying this phenomenon remains largely unknown. Here, we used forward genetic screening to identify a mutant displaying two temperature-sensitive and seemingly unrelated defects: locomotion and regeneration of amputated fins. A causative gene was defined as scn8ab, which encodes the neuronal, voltage-gated sodium channel Nav1.6. Mutation of scn8ab led to disrupted axon regrowth and patterning during the early phase of regeneration, resulting in hypo-innervation and impaired regeneration. This research uncovers a factor critical for innervation in the injured appendage and offers a perspective on the functions of Nav1.6. Teleost fishes and urodele amphibians can regenerate amputated appendages, whereas this ability is restricted to digit tips in adult mammals. One key component of appendage regeneration is reinnervation of the wound area. However, how innervation is regulated in injured appendages of adult vertebrates has seen limited research attention. From a forward genetics screen for temperature-sensitive defects in zebrafish fin regeneration, we identified a mutation that disrupted regeneration while also inducing paralysis at the restrictive temperature. Genetic mapping and complementation tests identify a mutation in the major neuronal voltage-gated sodium channel (VGSC) gene scn8ab. Conditional disruption of scn8ab impairs early regenerative events, including blastema formation, but does not affect morphogenesis of established regenerates. Whereas scn8ab mutations reduced neural activity as expected, they also disrupted axon regrowth and patterning in fin regenerates, resulting in hypoinnervation. Our findings indicate that the activity of VGSCs plays a proregenerative role by promoting innervation of appendage stumps.
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影响因子：
5.2
作者：
Kawai M;Green CB;Horowitz M;Ackert-Bicknell C;Lecka-Czernik B;Rosen CJ
通讯作者：
Rosen CJ
影响因子：
4.6
作者：
Farkas, Johanna E.;Freitas, Polina D.;Monaghan, James R.
通讯作者：
Monaghan, James R.
影响因子：
4.5
作者：
Chen CH;Merriman AF;Savage J;Willer J;Wahlig T;Katsanis N;Yin VP;Poss KD
通讯作者：
Poss KD
DOI：
10.1126/science.aaq0681
发表时间：
2018-10-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerber T;Murawala P;Knapp D;Masselink W;Schuez M;Hermann S;Gac-Santel M;Nowoshilow S;Kageyama J;Khattak S;Currie JD;Camp JG;Tanaka EM;Treutlein B
通讯作者：
Treutlein B
影响因子：
11.8
作者：
Kang, Junsu;Nachtrab, Gregory;Poss, Kenneth D.
通讯作者：
Poss, Kenneth D.