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

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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