Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution.
Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution.
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DOI：
10.1101/gad.279745.116
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发表时间：
2016-05-01
影响因子：
10.5
通讯作者：
Burden SJ
中科院分区：
文献类型：
--
作者：
Remédio L;Gribble KD;Lee JK;Kim N;Hallock PT;Delestrée N;Mentis GZ;Froemke RC;Granato M;Burden SJ
在这项研究中，Remédio等人。使用老鼠和斑马鱼来证明哺乳动物和斑马鱼的肌肉预成模式是由不同的机制建立的。他们的发现表明，AGRIN/Lrp4/Musk信号在鱼类和哺乳动物的神经肌肉突触形成中起着至关重要的作用，而Wnt信号是必不可少的。运动轴突会接近在预期突触区域预先形成图案的肌肉。在小鼠中，乙酰胆碱受体的预模式化需要LDLR家族成员Lrp4和受体酪氨酸激酶Musk。Lrp4可以结合和刺激麝香，强烈表明Lrp4和麝香之间的关联不依赖于额外的配体，启动了小鼠的前图案形成。在斑马鱼中，与麝香中的Frizzleed(FZ)样结构域结合的WNTs是形成前图案所必需的，这表明WNTs可能有助于哺乳动物的前图案形成和神经肌肉发育。我们表明，小鼠的预构图需要Lrp4，但不需要麝香FZ样结构域。相比之下，斑马鱼的预构图需要类似麝香的FZ结构域，而不需要Lrp4。尽管有这些差异，斑马鱼和小鼠的神经肌肉突触形成有相似的机制，需要Lrp4、麝香和神经元agin，但不需要麝香FZ样域或肌肉产生Wnt。我们的发现表明，进化分化的机制在斑马鱼和小鼠身上建立了肌肉前模式。
In this study, Remédio et al. use mice and zebrafish to show that muscle prepatterning in mammals and zebrafish is established by different mechanisms. Their findings demonstrate that Agrin/Lrp4/MuSK signaling plays an essential role in neuromuscular synapse formation in both fish and mammals, whereas Wnt signaling is dispensable. Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice.