Robert Brackenbury

Schwann Cells Express NDF and SMDF/n-ARIA mRNAs, Secrete Neuregulin, and Show Constitutive Activation of erbB3 Receptors: Evidence for a Neuregulin Autocrine Loop

Cultured Schwann cells secreted low levels (30 pg/ml/1.5 x 10(6) cells) of a 45-kDa neuregulin protein and showed constitutive activation of a neuregulin receptor, Erb-B3, suggesting the existence of an autocrine loop involving neuregulins in Schwann cells. RT-PCR analyses indicated that Schwann cells and fibroblasts in culture produced SMDF/n-ARIA and NDF but not GGF neuregulin messages. Schwann cell and fibroblast neuregulin messages encoded both beta and alpha domains; Schwann cell transcripts encoded only transmembrane neuregulin forms while fibroblast messages encoded transmembrane and secreted forms. SMDF/n-ARIA and NDF messages were also expressed in early postnatal rat sciatic nerve, suggesting a role for neuregulins in peripheral nerve development. An anti-neuregulin antibody inhibited the mitogenic response of Schwann cells to cultured neurons and to extracts of cultured neurons or embryonic brain, consistent with the accepted paracrine role of neuregulins on Schwann cells. Surprisingly, the same antibody inhibited Schwann cell proliferation stimulated by several unrelated mitogens including bFGF, HGF, and TGF-beta1. These data implicate both paracrine and autocrine pathways involving neuregulin form(s) in Schwann cell mitogenic responses.

Expression of Neural Cell Adhesion Molecules in Normal and Pathologic Tissues

Because cell‐cell and cell‐matrix interactions directly affect the growth, differentiation, and morphogenesis of neural tissue, abnormal changes in these processes could have severe pathologic consequences. Over the last few years, it has become possible to investigate these interactions at the molecular level due to advances in the identification and characterization of matrix components and receptors and cell adhesion molecules (CAMs). Emerging evidence suggests that two broad classes of CAMs are represented by the neural CAM, N‐CAM, and the epithelial CAM, L‐CAM. N‐CAM and several other neural adhesion molecules contain immunoglobulin‐like domains and do not require calcium for binding. In contrast, L‐CAM, N‐cadherin, and P‐cadherin depend on calcium for activity and share structural features that differ from those of the N‐CAM family. All of these CAMs are expressed in early embryos and in a variety of tissues throughout development, although each has a characteristic pattern. Initial studies suggest that injury, oncogenic transformation, and some genetic neurologic disorders are accompanied by changes in CAM expression that alter the adhesive or migratory behavior of cells.

Chapter 25. Cell Adhesion Molecules

Publisher Summary Cell Adhesion Molecules (CAMS) have been defined empirically as molecules that mediate cell-cell adhesion in extremely artificial assays. As a result, the properties of the assays define the kinds of molecules that may be identified. Many CAMs have been identified, characterized, and classified into families. The CAMs are widely distributed among various tissues and their structure and binding activities are conserved across the animal kingdom from Drosophila to man. Recent evidence suggests that many of the CAMs may play active roles in cell-cell communication as well as adhesion. Individual cells may express several CAMs and these CAMs may play roles in parallel signaling pathways. Such a key role implies that alterations in CAM expression or function may accompany or cause severe pathologies, but this possibility has only begun to be explored. Finally, the involvement of CAMs in key signaling processes together with their accessibility at the cell surface may allow the development and administration of specialized ligands or antibodies that could interact with the cell surface and produce decisive intracellular effects on cell differentiation or function. To be convincingly identified as a CAM, a candidate molecule must satisfy several criteria: the CAM must be expressed in tissues and, during development, in a distribution that is consistent with its presumed adhesive role; antibodies to the CAM should produce perturbations of development or function in vivo that may be readily interpreted as a result of the disrupting adhesion; the purified CAM should display a binding activity to the target cell; transfection of control cells with CAM sequences should confer adhesive ability; and finally, mutations that alter CAM expression or function should produce direct effects on adhesion. This chapter e discusses the many CAMS that have been identified by this general approach that have fallen into a small number of families or classes.

Molecules of cell adhesion and recognition: An overview

Publisher Summary This chapter provides an overview of cell adhesion—from early experiments implicating differential cell–cell adhesion as an important developmental mechanism to the methods used to isolate and characterize cell adhesion molecules (CAMs). More than 50 CAMs have been identified and structural characterization has allowed these molecules to be classified into families. The initial definition of CAMs was operational, based on their ability to mediate cell–cell adhesion in assays in vitro . Many of the CAMs (the desmogleins and desmocollins of desmosomes) and the cadherins, found within adherens junctions, do appear to function as adhesive molecules in vivo . CAMs do not serve simply as intercellular glue—for example, contacts involving N-cadherin, Ll/Ng-CAM, or N-CAM trigger changes in intracellular second-messenger systems that affect neurite extension and contact mediated by E-cadherin affects cell motility. The structure of the membrane-associated protein tyrosine phosphatase μ that includes an immunoglobulin domain that mediates cell–cell adhesion and a cadherin-related segment in its cytoplasmic region is strongly suggestive of a role in cell-contact regulation of cellular differentiation. In the case of some integrin receptors, ligand binding is known to affect gene expression. The field of cell adhesion is moving beyond identifying and structurally characterizing CAMs and into the more exciting realm of precisely defining their roles in cellular physiology and differentiation.