ABSTRACT
CD98hc is a type II transmembrane protein that covalently links to one of several L-type amino acid transporters. CD98hc was first identified as a lymphocyte activation marker. In this study, we examined the role that CD98hc plays in the functions of macrophages using tissue specific knock-out miceCD98hc (CD98hc(flox/-)LysM-cre mice). When isolated peritoneal macrophages were incubated for 48 h, the macrophages obtained from the knock-out mice showed round-shaped morphologies, while almost all of the cells obtained from the control mice were spindle-shaped. The macrophage functions such as the antigen-presenting, phagocytic, and fusion activities, have been reported to decrease in CD98hc-deficient peritoneal macrophages. In addition, when the CD98hc deficient macrophages were stimulated with either IFN-γ/LPS or IL-4, the production of NO(2) or arginase-I decreased in comparison to that observed in the control macrophages. These findings show that the CD98hc molecules play an important role in the activation and functions of macrophages.
Subject(s)
Fusion Regulatory Protein 1, Heavy Chain/immunology , Macrophages, Peritoneal/immunology , Animals , Cells, Cultured , Fusion Regulatory Protein 1, Heavy Chain/genetics , Mice , Mice, Knockout , PhagocytosisABSTRACT
In development of the peripheral nervous system, Schwann cells proliferate, migrate, and ultimately differentiate to form myelin sheath. In all of the myelination stages, Schwann cells continuously undergo morphological changes; however, little is known about their underlying molecular mechanisms. We previously cloned the dock7 gene encoding the atypical Rho family guanine-nucleotide exchange factor (GEF) and reported the positive role of Dock7, the target Rho GTPases Rac/Cdc42, and the downstream c-Jun N-terminal kinase in Schwann cell migration (Yamauchi et al., 2008). We investigated the role of Dock7 in Schwann cell differentiation and myelination. Knockdown of Dock7 by the specific small interfering (si)RNA in primary Schwann cells promotes dibutyryl cAMP-induced morphological differentiation, indicating the negative role of Dock7 in Schwann cell differentiation. It also results in a shorter duration of activation of Rac/Cdc42 and JNK, which is the negative regulator of myelination, and the earlier activation of Rho and Rho-kinase, which is the positive regulator of myelination. To obtain the in vivo evidence, we generated Dock7 short hairpin (sh)RNA transgenic mice. They exhibited a decreased expression of Dock7 in the sciatic nerves and enhanced myelin thickness, consistent with in vitro observation. The effects of the in vivo knockdown on the signals to Rho GTPases are similar to those of the in vitro knockdown. Collectively, the signaling through Dock7 negatively regulates Schwann cell differentiation and the onset of myelination, demonstrating the unexpected role of Dock7 in the interplay between Schwann cell migration and myelination.