LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans.
LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans.
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作者：
Li P;Collins KM;Koelle MR;Shen K
不同的细胞类型和它们之间精确的突触连接是神经系统的主要特征。关于细胞命运的多样化如何与突触靶点的选择相联系，人们知之甚少。在这里，我们研究突触前神经元如何选择一种类型的肌肉，vm 2，作为突触的目标，并形成突触的树突棘状肌肉手臂。我们发现Notch-Delta通路是区分靶肌肉和非靶肌肉所必需的。APX-1/Delta在包括非靶vm 1的周围细胞中起作用，以激活靶vm 2中的LIN-12/Notch。LIN-12细胞自主地起作用以上调vm 2中的MADD-40/DCC和MADD-2的表达，这反过来又一起起作用以促进肌臂形成和引导。在非靶vm 1肌肉中异位表达β-40/DCC足以诱导这些细胞的肌臂延伸。因此，LIN-12/Notch信号通过选择性上调引导分子并在靶细胞中形成肌臂来指定靶选择。DOI：http://dx.doi.org/10.7554/eLife.00378.001神经系统的发育涉及不同细胞类型之间复杂连接网络的形成，如运动神经元、中间神经元和锥体细胞。然而，单个细胞被编程以获得特定身份的机制，以及它们如何被指示与其他特定细胞形成连接，仍然不清楚。在许多物种中，Notch信号通路在建立这些网络中发挥作用。Notch是一种跨膜蛋白，这意味着它在细胞内有一种成分，在细胞外有另一种成分。当配体与Notch的细胞外部分结合时，这会导致受体断裂成两部分。细胞内结构域然后移动到细胞核，在那里它可以影响基因表达。线虫（C. elegans），它有两个Notch受体，经常被用来研究神经网络的形成，因为每个蠕虫只有大约300个神经元，并且它们在每个蠕虫中以大致相同的方式连接。C.线虫依靠两种非常相似的细胞--第一型和第二型外阴肌细胞--产卵，而触发产卵的神经元在称为肌臂的特殊结构上形成突触连接。然而，这些结构仅在2型外阴肌中发现。为了研究产卵回路形成的机制，李等人筛选了大量突变蠕虫，以寻找缺乏肌臂的动物。他们鉴定了许多这样的突变体，与野生型蠕虫相比，它们产的卵更少，并发现它们都在编码LIN-12/Notch通路中涉及的蛋白质或配体的基因中发生突变。该途径介导细胞-细胞相互作用，有助于指定细胞命运。Li等人表明，当2型外阴肌细胞的邻居1型外阴肌细胞和外阴上皮细胞产生足够的配体以激活2型外阴肌细胞上的LIN-12 Notch受体时，2型外阴肌细胞发育出肌臂。他们还确定了LIN-12的两个下游靶点，并发现在1型外阴肌细胞中人工表达其中一个靶点足以触发肌臂的形成。Li等人的工作提供了进一步的证据，证明Notch信号通路在早期发育中的作用是众所周知的，它也在后期发育阶段起作用，以决定细胞命运和连接模式。DOI：http://dx.doi.org/10.7554/eLife.00378.002网站
The diverse cell types and the precise synaptic connectivity between them are the cardinal features of the nervous system. Little is known about how cell fate diversification is linked to synaptic target choices. Here we investigate how presynaptic neurons select one type of muscles, vm2, as a synaptic target and form synapses on its dendritic spine-like muscle arms. We found that the Notch-Delta pathway was required to distinguish target from non-target muscles. APX-1/Delta acts in surrounding cells including the non-target vm1 to activate LIN-12/Notch in the target vm2. LIN-12 functions cell-autonomously to up-regulate the expression of UNC-40/DCC and MADD-2 in vm2, which in turn function together to promote muscle arm formation and guidance. Ectopic expression of UNC-40/DCC in non-target vm1 muscle is sufficient to induce muscle arm extension from these cells. Therefore, the LIN-12/Notch signaling specifies target selection by selectively up-regulating guidance molecules and forming muscle arms in target cells. DOI: http://dx.doi.org/10.7554/eLife.00378.001 The development of the nervous system involves the formation of complex networks of connections between diverse cell types, such as motor neurons, interneurons and pyramidal cells. However, the mechanisms by which individual cells are programmed to acquire particular identities, and how they are instructed to form connections with other specific cells, remain unclear. In many species, the Notch signaling pathway has a role in setting up these networks. Notch is a transmembrane protein, which means that it has one component inside the cell and another outside. When a ligand binds to the extracellular part of Notch, this causes the receptor to break in two. The intracellular domain then travels to the nucleus where it can influence gene expression. The nematode worm (C. elegans), which has two Notch receptors, is often used to study the formation of neuronal networks because each worm has only around 300 neurons, and they are connected in roughly the same way in each worm. C. elegans relies on two types of cell that are very similar to each other—type-1 and type-2 vulval muscle cells—to lay eggs, and the neurons that trigger egg-laying form synaptic connections on specialized structures called muscle arms. However, these structures are found only in type-2 vulval muscle. To investigate the mechanisms underlying the formation of the egg-laying circuit, Li et al. screened large numbers of mutant worms to find animals that lacked muscle arms. They identified a number of such mutants, which laid fewer eggs compared to wild-type worms, and found that they all had mutations in genes that encode for proteins or ligands that are involved in the LIN-12/Notch pathway. This pathway mediates cell–cell interactions that help to specify cell fates. Li et al. showed that type-2 vulval muscle cells develop muscle arms when their neighbors—type-1 vulval muscle cells and vulval epithelial cells—produce enough ligand to activate the LIN-12 Notch receptor on the type-2 vulval muscle cells. They also identified two of the downstream targets of LIN-12, and found that artificially expressing one of these in type-1 vulval muscle cells is sufficient to trigger the formation of muscle arms. The work of Li et al. provides further evidence that the Notch signalling pathway, which is well known for its role in early development, also acts at later developmental stages to determine cell fate and patterns of connectivity. DOI: http://dx.doi.org/10.7554/eLife.00378.002