In the present study, the availability of SC-specific JAM-C-KO mice enabled us to observe and, for the first time, report on the expression of JAM-C at junctions between adjacent perineural cells

In the present study, the availability of SC-specific JAM-C-KO mice enabled us to observe and, for the first time, report on the expression of JAM-C at junctions between adjacent perineural cells. SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.Colom, B., Poitelon, Y., Huang, W., Woodfin, A., Averill, S., Del Carro, U., Zambroni, D., Brain, S. D., Perretti, M., Ahluwalia, A., Priestley, J. V., Chavakis, T., Imhof, B. A., Feltri, M. L., Nourshargh, S. Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves. Keywords:adhesion molecules, tight junctions, peripheral nerves Junctional adhesion molecule-C (JAM-C) is a type I transmembrane protein and member of an immunoglobulin subfamily currently composed of JAM-A, JAM-B, JAM-C, JAM-4, JAM-L, ESAM (endothelial cell selective adhesion molecule) and CAR (coxsackie virus and adenovirus receptor). The molecule consists of 2 extracellular immunoglobulin domains and a short cytoplasmic tail, which supports extracellular and intracellular interactions with surface ligands and cytoskeletal/signaling partners, respectively (1,2). The principal JAM-C ligands to date are JAM-C, JAM-B, and the integrin M2, although their relative contributions to the diverse functions of JAM-C (see below) remain unclear (36). JAM-C was originally detected on endothelial cells (ECs; ref.7) and on human activated T cells (6) and has since been reported to be expressed on other subsets of human leukocytes (4,8) and platelets (3), vascular smooth muscle cells (9), and a wide range of nonvascular cells, such as spermatids (10), epithelial cells (11), and fibroblasts (12). In addition, we have reported recently on the expression of JAM-C in peripheral nerves, where it is localized on Schwann cells (SCs) at sites characteristic of junctional regions of noncompact myelin, such as the paranodal regions, Schmidt-Lanterman incisures (SLIs), and the mesaxonal SR-2211 regions (13). In line with its broad expression pattern, JAM-C has been associated SR-2211 with numerous biological functions. Most notably, JAM-C has been studied in the context of vascular and inflammatory responses, where direct evidence indicates its SR-2211 involvement in leukocyte transmigration (14), vascular permeability (15), and angiogenesis (16). Although much of these early works were performed usingin vitroassays, more recently the role of JAM-C in inflammation and vascular biology has been investigatedin vivowithin numerous disease models. These include murine models of arthritis, acute pancreatitis, peritonitis, ischemia/reperfusion injury, atherosclerosis, and pulmonary inflammation (1722), with some Rabbit Polyclonal to GRP94 of these studies involving the use of genetically modified animals. Characterization of JAM-C-knockout (KO) mice has also identified additional functions for JAM-C, such as roles in cell polarity, immunity, and inflammation (10,19,23). As a result of its multiple and wide-ranging biological roles, mice with complete deletion of JAM-C exhibit a severe phenotype that includes growth retardation, development of megaoesophagus, defects in hematopoiesis (17,24), and defective motor functions and abnormalities in neural morphology and electrophysiology (13). Collectively, the findings of the latter study indicated an important role for JAM-C in maintaining the integrity and function of peripheral nerves and suggested SR-2211 an association between defective expression of JAM-C and pathogenesis of inherited and/or acquired peripheral neuropathies. However, as the severe and complex phenotype of the complete JAM-C-KO mice makes the study of the functional role of JAM-C in nerves difficult, to extend our previous works we now report on the generation and investigations of a novel mouse colony in which the expression of JAM-C is selectively deleted in SCs. Nerves from these animals exhibited mild morphological and functional defects and behavioral tests revealed muscle SR-2211 weakness and hypersensitivity to mechanical nociceptive stimuli. The findings of the present study also statement on previously unfamiliar expressions of JAM-C in peripheral nerves, specifically in finely myelinated sensory materials and at cellcell junctions of perineural cells. Overall, through the generation and characterization of a novel conditional-KO mouse colony with SC-specific deletion of JAM-C, the findings of this study provide higher insight into the manifestation and function of JAM-C in peripheral nerves. == MATERIALS AND METHODS == == Antibodies == Antibodies used in this study are outlined inTable 1. For two times or triple staining, some antibodies were directly conjugated with Alexa dyes using the Alexa-Fluor monoclonal antibody.