Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension.
Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension.
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DOI：
10.1371/journal.pbio.1001538
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Episkopou V
中科院分区：
文献类型：
--
作者：
Kelly CE;Thymiakou E;Dixon JE;Tanaka S;Godwin J;Episkopou V
运动轴突在肢体发育过程中的有效延伸需要通过泛素连接酶Ark2C增强BMP信号反应。运动神经元（MN）轴突在外周延伸很长一段距离，以形成与目标肌肉的精确连接，关于运动神经元（MN）轴突前进所需的外在信号知之甚少。本研究表明，Rnf165 （Arkadia-like; Arkadia2; Ark2C）在神经系统中特异性表达，其在小鼠体内的缺失会导致发育过程中产生的运动神经缺损，并导致断奶前的消耗和死亡。缺陷的范围从运动轴突延伸的严重减少（见于前肢背）到膈神经突触前分支的缩短（见于膈肌）。分子功能分析表明，在脊髓环境下，Ark2C增强了Smad1/5/8效应子的转录应答，这些效应子在骨形态发生蛋白（BMP）信号下游被激活（磷酸化）。与ark2c调节的BMP信号影响运动轴突一致，脊髓运动池被发现含有磷酸化的Smad1/5/8 (pSmad)，用BMP抑制剂治疗原发性MN会减少轴突长度。此外，Ark2C +/−小鼠中BMP-Smad信号的遗传减少导致Ark2C - /−样前肢背神经支配缺陷的出现，证实了Ark2C增强BMP-Smad反应介导有效的神经支配。综上所述，上述数据揭示了BMP-Smad信号参与运动轴突的推进。运动神经元通过长轴突控制运动，这些长轴突从脊髓延伸到远至四肢的肌肉。对于调节外周广泛轴突生长的因素知之甚少。在这里，我们报道了泛素连接酶Ark2C （Arkadia2）在神经元中表达，并可以放大神经元对特定信号的反应。我们发现这些信号属于骨形态发生蛋白（BMP）家族的分泌因子，这些因子在外周高度表达，并调节四肢的发育。小鼠Ark2C基因功能的缺失导致运动轴突向远端肌肉的生长效率低下，我们发现这一过程是由BMP信号调节的。Ark2C以破坏BMP抑制剂为目标，因此Ark2C的存在有助于增强BMP信号，这反过来对远端肌肉的神经支配是必要的。我们的实验揭示了BMP在运动轴突生长中的一个未知功能，并描述了轴突和四肢如何协调生长的分子机制。
Efficient extension of motor axons into the limb during development requires enhancement of BMP signaling responses by the ubiquitin ligase Ark2C. Little is known about extrinsic signals required for the advancement of motor neuron (MN) axons, which extend over long distances in the periphery to form precise connections with target muscles. Here we present that Rnf165 (Arkadia-like; Arkadia2; Ark2C) is expressed specifically in the nervous system and that its loss in mice causes motor innervation defects that originate during development and lead to wasting and death before weaning. The defects range from severe reduction of motor axon extension as observed in the dorsal forelimb to shortening of presynaptic branches of the phrenic nerve, as observed in the diaphragm. Molecular functional analysis showed that in the context of the spinal cord Ark2C enhances transcriptional responses of the Smad1/5/8 effectors, which are activated (phosphorylated) downstream of Bone Morphogenetic Protein (BMP) signals. Consistent with Ark2C-modulated BMP signaling influencing motor axons, motor pools in the spinal cord were found to harbor phosphorylated Smad1/5/8 (pSmad) and treatment of primary MN with BMP inhibitor diminished axon length. In addition, genetic reduction of BMP-Smad signaling in Ark2C +/− mice caused the emergence of Ark2C −/−-like dorsal forelimb innervation deficits confirming that enhancement of BMP-Smad responses by Ark2C mediates efficient innervation. Together the above data reveal an involvement of BMP-Smad signaling in motor axon advancement. Motor neurons control movement via long axons that extend from the spinal cord to muscles as far as in distant limbs. Little is known about factors that regulate this extensive axonal growth in the periphery. Here we report that the ubiquitin ligase Ark2C (Arkadia2) is expressed in neurons and can serve to amplify neuronal responses to specific signals. We find that these signals belong to the Bone Morphogenetic Protein (BMP) family of secreted factors, which are highly expressed in the periphery and known to regulate the development of the limbs. Loss of Ark2C gene function in mice results in inefficient growth of motor axons to distant muscles, and we show that this process is regulated by BMP signaling. Ark2C targets BMP inhibitors for destruction, and therefore the presence of Ark2C helps to enhance BMP signaling, which in turn is necessary for the innervation of distal muscles. Our experiments reveal a previously unknown function of BMP in motor axon growth and describe a molecular mechanism for how axons and limbs coordinate their growth.
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