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Originally published online as doi:10.2353/ajpath.2009.080743 on May 12, 2009

Published online before print May 12, 2009
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(American Journal of Pathology. 2009;174:2278-2289.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080743

Expression of a Soluble Isoform of Cell Adhesion Molecule 1 in the Brain and Its Involvement in Directional Neurite Outgrowth

Man Hagiyama, Naoki Ichiyanagi, Keiko B. Kimura, Yoshinori Murakami and Akihiko Ito

From the Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, is expressed on superior cervical ganglion neurites and mediates cell–cell adhesion by trans-homophilic binding. In addition to the membrane-bound form, we have previously shown that a soluble form (sCADM1) generated by alternative splicing possesses a stop codon immediately downstream of the immunoglobulin-like domain. Here, we demonstrate the presence of sCADM1 in vivo and its possible role in neurite extension. sCADM1 appears to be a stromal protein because extracellular-restricted, but not intracellular-restricted, anti-CADM1 antibody stained stromal protein-rich extract from mouse brains. Murine plasmacytoma cells, P3U1, were modified to secrete sCADM1 fused with either immunoglobulin (Ig)G Fc portion (sCADM1-Fc) or its deletion form that lacks the immunoglobulin-like domain ({Delta}sCADM1-Fc). When P3U1 derivatives expressing sCADM1-Fc or {Delta}sCADM1-Fc were implanted into collagen gels, Fc-fused proteins were present more abundantly around the cells. Superior cervical ganglion neurons, parental P3U1, and either derivative were implanted into collagen gels separately, and co-cultured for 4 days. Bodian staining of the gel sections revealed that most superior cervical ganglion neurites turned toward the source of sCADM1-Fc, but not {Delta}sCADM1-Fc. Furthermore, immunofluorescence signals for sCADM1-Fc and membrane-bound CADM1 were co-localized on the neurite surface. These results show that sCADM1 appears to be involved in directional neurite extension by serving as an anchor to which membrane-bound CADM1 on the neurites can bind.







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