Regulatory roles of Meltrins, membrane-anchored ADAMs, in cell-cell interactions

Meltrins（膜锚定 ADAM）在细胞间相互作用中的调节作用

基本信息

批准号：
17082003
负责人：
SEHARA Atsuko
金额：
$ 83.65万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2009
项目状态：
已结题

项目摘要

Development and regeneration require various kinds of intercellular signaling and adhesion molecules. Many intercellular signaling molecules are generated as membrane-anchored proteins, and they are subjected to proteolytic processing to liberate their extracellular domains (ectodomain shedding). Our research has been focused on regulatory roles of ADAM (A Disintegrin And Metalloprotease) family proteins in such cell-cell interactions and the ectodomain shedding.We clarified roles and functions of Meltrin beta (ADAM19 / a disintegrin and metalloprotease 19) in development and regeneration of peripheral nervous system (PNS). In Meltrin beta-deficient mice, neuromuscular junction formation and sciatic nerve regeneration was affected. In the case of sciatic nerve regeneration, re-myelination of axons delayed because terminal differentiation of Schwann cells, including activation of Krox-20, was affected in the absence of Meltrin beta. The membrane preparation of nerves isolated from meltr … More in beta deficient mice showed decreased activation of Akt pathway in Schwann cells compared to that from wild type mice. These results suggest that Meltrin beta is involved in the regulation of juxtacrine signaling by which nerves in the PNS governs Schwann cell development.On the other hand, we evaluated roles and functions of ADAMs by monitoring cellular behaviors in living zebrafish embryos. By monitoring fluorescent protein-labeled blood precursors and blood vessels in zebrafish, we showed a novel mechanism for the onset of blood circulation, which involves proteolysis that regulates blood-vessel contacts. The live imaging reveals that the first blood circulation occurs synchronously. This synchrony is achieved by retention of erythroid precursors on the lumen of blood vessels after intravasation one after another from the sub-aortic region, and then, by almost simultaneous release of these precursors into the plasma flow. Injection of metalloprotease inhibitors into the circulation after formation of the heart and vasculature disturbed the synchronous onset of blood circulation, suggesting that metalloprotease activity in the lumen of the vasculature is prerequisite for the simultaneous release of blood cells into the flow. One of zebrafish ADAM (a disintegrin and metalloprotease family), ADAM8, was identified as a metalloprotease participating in that process. Blood stagnation was observed in ADAM8-depleted embryos. Cell biological analyses and expression of an inactive protease of ADAM8 under a gata-1 promoter suggest that ADAM8 expressed in the primitive blood abrogates their adhesion to the vasculature cell autonomously. Based on these findings, we propose that the first blood requires both flow-dependent passive and proteolysis-dependent active processes to enter into circulation. Less

开发和再生需要各种细胞间信号分子，将其作为膜锚定的蛋白质，而YES则释放了其细胞外域。脱落的脱域脱落和梅尔特林β（ADAM19 / A ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM19 / ADAM 19）轴突延迟了schwann细胞的末端分化，包括Krox-20的激活，在梅尔特蛋白β的缺陷中受到影响。类型的小鼠。这些结果表明，Meltrin beta是近二氨酸的近距离信号传导，而PNS Schwann细胞开发中的神经。另一方面，我们通过监测Zebrafish胚胎来评估Adams行为的作用和功能蛋白质标记的血液前体和斑马鱼中的血液血液血液，我们显示出一种新的机制，用于血液循环发作的一种新机制，即同步的同步，是由插入e的血液中的红颗粒前体在插入e的血液腔上的另一个，从另一个插入的血液中，从另一个亚属性区域插入。然后，通过Kaneme将这些前体释放到tasma流中，直到心脏的循环和脉管系统都会扰乱血液循环的同步发作，这表明血管同时流入流入流动的血管腔中的塔罗皮亚SE活性。 e族）ADAM8被确定为参与该过程的金属蛋白酶，在GATA-1启动子下ADAM8的不活跃蛋白酶的表达表明，在原始血液中表达的ADAM8会消除其对脉管细胞的粘附。基于这些发现，我们提出第一个血液需要依赖流动性的被动和依赖性的活性过程才能进入循环