Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.
Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.
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DOI：
10.1523/jneurosci.6287-09.2010
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发表时间：
2010-03-10
期刊：
影响因子：
--
通讯作者：
Meijer D
中科院分区：
文献类型：
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作者：
Ozkaynak E;Abello G;Jaegle M;van Berge L;Hamer D;Kegel L;Driegen S;Sagane K;Bermingham JR Jr;Meijer D
在发育中的周围神经系统（PNS）中，轴突的分离和髓鞘形成是雪旺细胞和轴突之间一系列复杂的细胞和分子相互作用的结果。先前，我们鉴定了Lgi 4基因（富含亮氨酸的胶质瘤失活4）作为PNS中髓鞘形成的重要调节因子，并且如在爪爪小鼠中观察到的，其功能障碍导致关节弯曲。Lgi 4是一种分泌蛋白，是主要在神经系统中表达的蛋白质小家族的成员。它们的作用机制尚不清楚，但可能涉及与跨膜蛋白的Adam（A去整合素和金属蛋白酶）家族成员，特别是Adam 22结合。我们发现，Lgi 4和Adam 22都在雪旺细胞以及感觉神经元中表达，并且Lgi 4直接与Adam 22结合而不需要额外的膜相关因子。为了确定Lgi 4-Adam 22功能是否涉及旁分泌和/或自分泌作用机制，我们在小鼠中进行了异型许旺细胞感觉神经元培养和Lgi 4和Adam 22的细胞类型特异性消融。我们表明，雪旺氏细胞是Lgi 4在发育中的神经和Adam 22轴突上所需的主要细胞来源。因此，我们的研究结果揭示了一种新的旁分泌信号轴在周围神经髓鞘形成中，其中许旺细胞分泌的Lgi 4通过结合轴突Adam 22来驱动许旺细胞的分化。
The segregation and myelination of axons in the developing peripheral nervous system (PNS), results from a complex series of cellular and molecular interactions between Schwann cells and axons. Previously we identified the Lgi4 gene (Leucine-rich-glioma inactivated4) as an important regulator of myelination in the PNS, and its dysfunction results in arthrogryposis as observed in claw paw mice. Lgi4 is a secreted protein and a member of a small family of proteins that are predominantly expressed in the nervous system. Their mechanism of action is unknown but may involve binding to members of the Adam (A disintegrin and metalloprotease) family of transmembrane proteins, in particular Adam22. We found that Lgi4 and Adam22 are both expressed in Schwann cells as well as in sensory neurons and that Lgi4 binds directly to Adam22 without a requirement for additional membrane associated factors. To determine whether Lgi4-Adam22 function involves a paracrine and/or an autocrine mechanism of action we performed heterotypic Schwann cell-sensory neuron cultures and cell-type specific ablation of Lgi4 and Adam22 in mice. We show that Schwann cells are the principal cellular source of Lgi4 in the developing nerve and that Adam22 is required on axons. Our results thus reveal a novel paracrine signalling axis in peripheral nerve myelination in which Schwann cell secreted Lgi4 functions through binding of axonal Adam22 to drive the differentiation of Schwann cells.