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Rnf165/Ark2C 增强 BMP-Smad 信号转导以介导运动轴突延伸。

Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension.

机构信息

Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.

出版信息

PLoS Biol. 2013;11(4):e1001538. doi: 10.1371/journal.pbio.1001538. Epub 2013 Apr 16.

DOI:10.1371/journal.pbio.1001538
PMID:23610558
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3627648/
Abstract

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.

摘要

目前对于运动神经元 (MN) 轴突延伸所需的外在信号知之甚少，MN 轴突在周围延伸很长的距离，与目标肌肉形成精确的连接。在这里，我们发现 Rnf165（Arkadia 样；Arkadia2；Ark2C）特异性表达于神经系统，其在小鼠中的缺失导致运动神经支配缺陷，这些缺陷起源于发育过程中，并导致断奶前肌肉萎缩和死亡。缺陷的范围从背部前肢观察到的严重减少运动轴突延伸到膈肌观察到的膈神经前突触分支缩短。分子功能分析表明，在脊髓中，Ark2C 增强了 Smad1/5/8 效应物的转录反应，Smad1/5/8 是骨形态发生蛋白 (BMP) 信号下游激活（磷酸化）的。与 Ark2C 调节的 BMP 信号影响运动轴突一致，脊髓中的运动池被发现含有磷酸化的 Smad1/5/8（pSmad），并且 BMP 抑制剂处理原代 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出现 Ark2C(-/-) 样背部前肢神经支配缺陷，这证实了 Ark2C 增强 BMP-Smad 反应介导有效的神经支配。综上所述，这些数据揭示了 BMP-Smad 信号在运动轴突延伸中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/3be2fa5fd59f/pbio.1001538.g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/b5425097bc14/pbio.1001538.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/e900469af4fb/pbio.1001538.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/9806b9bddb02/pbio.1001538.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/df02095b652e/pbio.1001538.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/a068a6d9449c/pbio.1001538.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/9940ec74d25b/pbio.1001538.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/72212cde9083/pbio.1001538.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/75f35bfaa74d/pbio.1001538.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/4be3d44cb688/pbio.1001538.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/f53c2c8430b8/pbio.1001538.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/3be2fa5fd59f/pbio.1001538.g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/b5425097bc14/pbio.1001538.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/e900469af4fb/pbio.1001538.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/f5f97012f262/pbio.1001538.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/9806b9bddb02/pbio.1001538.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/df02095b652e/pbio.1001538.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/a068a6d9449c/pbio.1001538.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/9940ec74d25b/pbio.1001538.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/72212cde9083/pbio.1001538.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/75f35bfaa74d/pbio.1001538.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/4be3d44cb688/pbio.1001538.g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/f53c2c8430b8/pbio.1001538.g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d569/3627648/3be2fa5fd59f/pbio.1001538.g012.jpg

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