The heparan sulfate proteoglycan syndecan is an in vivo ligand for the Drosophila LAR receptor tyrosine phosphatase
The heparan sulfate proteoglycan syndecan is an in vivo ligand for the Drosophila LAR receptor tyrosine phosphatase
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DOI：
10.1016/j.cub.2005.08.035
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发表时间：
2005-10-11
期刊：
影响因子：
9.2
通讯作者：
Zinn, K
中科院分区：
文献类型：
--
作者：
Fox, AN;Zinn, K
背景：受体酪氨酸磷酸酶（RPTPs）在果蝇轴突引导和突触发生中起重要作用。胚胎运动轴突在其肌肉目标生长过程中所做的每个引导决定都需要五个神经RPTPs的特定子集。然而，这些要求背后的逻辑尚不清楚，部分原因是RPTPs在生长锥选择点识别的配体尚未确定。一般来说，rptp仍然是“孤儿受体”，因为尽管它们在体外被发现与许多不同的蛋白质相互作用，但它们在体内的配体是未知的。结果：我们利用一种新的缺陷筛选方法鉴定了跨膜硫酸肝素蛋白多糖Syndecan （Sdc）作为神经元RPTP LAR的配体。LAR在体外与Syndecan的糖胺聚糖链相互作用，具有纳米摩尔亲和力。利用Sdc和Lar LOF突变进行的遗传相互作用研究表明，Sdc有助于Lar在运动轴突引导中的功能。我们还表明，肌肉上的Sdc过表达与神经元中LAR过表达产生相同的表型，并且LAR的遗传去除抑制了异位肌肉Sdc产生的表型。最后，我们发现至少有一个额外的，非蛋白聚糖的LAR配体编码在基因组中。综上所述，我们的研究结果表明，肌肉上的Sdc可以在体内与神经元LAR相互作用，并且与Sdc的结合增加了LAR的信号传导作用。因此，Sdc是一种可以反式作用的配体，通过LAR积极调节神经元生长锥内的信号转导。
Background: Receptor tyrosine phosphatases (RPTPs) are essential for axon guidance and synaptogenesis in Drosophila. Each guidance decision made by embryonic motor axons during outgrowth to their muscle targets requires a specific subset of the five neural RPTPs. The logic underlying these requirements, however, is still unclear, partially because the ligands recognized by RPTPs at growth cone choice points have not been identified. RPTPs in general are still "orphan receptors" because, while they have been found to interact in vitro with many different proteins, their in vivo ligands are unknown.Results: Here we use a new type of deficiency screen to identify the transmembrane heparan sulfate proteoglycan Syndecan (Sdc) as a ligand for the neuronal RPTP LAR. LAR interacts with the glycosaminoglycan chains of Syndecan in vitro with nanomolar affinity. Genetic interaction studies using Sdc and Lar LOF mutations demonstrate that Sdc contributes to LAR's function in motor axon guidance. We also show that overexpression of Sdc on muscles generates the same phenotype as overexpression of LAR in neurons and that genetic removal of LAR suppresses the phenotype produced by ectopic muscle Sdc. Finally, we show that there is at least one additional, nonproteoglycan, ligand for LAR encoded in the genome.Conclusions: Taken together, our results demonstrate that Sdc on muscles can interact with neuronal LAR in vivo and that binding to Sdc increases LAR's signaling efficacy. Thus, Sdc is a ligand that can act in trans to positively regulate signal transduction through LAR within neuronal growth cones.