Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts I. Neural cell adhesion molecules

Abstract

To gain insight into the possible molecular mechanisms underlying axonal regeneration of neurons of the adult central nervous system (CNS), we have investigated, by in situ hybridization and by immunocytochemistry, the localization and sites of synthesis of the neurite outgrowth-promoting cell surface molecules L1, N-CAM and its highly sialylated form, N-CAM-PSA, in and around peripheral nerve grafts implanted into the thalamus of adult rats. Normal unoperated adult rat thalamus contains N-CAM and L1 but no N-CAM-PSA immunoreactive axons. Between 7 days and 13 weeks after graft implantation, L1, N-CAM and N-CAM-PSA were all present at the surface of axonal sprouts in the brain parenchyma close to grafts and in the central parts of Schwann cell columns within grafts. Schwann cell membranes were L1 and N-CAM positive at all postgraft survival times, more strongly at 2-4 weeks than other times, but were associated with N-CAM-PSA reaction product only where they abutted N-CAM-PSA positive axons. Schwann cell membranes apposed to basal laminae (which were avoided by regenerating CNS axons) were L1, N-CAM and N-CAM-PSA negative. Between 3 days and 8 weeks after grafting, N-CAM and L1 mRNA were generally weakly upregulated in neurons of the ipsilateral thalamus, but, most conspicuously, L1 mRNA was strongly upregulated in the neurons of the thalamic reticular nucleus; these neurons are known to regenerate axons very effectively into peripheral nerve grafts and are the probable source of most of the axons which enter thalamic grafts. N-CAM and L1 mRNA were also strongly upregulated in presumptive Schwann cells in the graft. These results show that regenerating CNS axons (re)express N-CAM-PSA and upregulate L1 and N-CAM, suggesting that all of these molecules may play a role in cellular interactions during the regeneration of CNS axons. Furthermore L1 synthesis appears to be particularly well correlated with the ability of CNS neurons to regenerate axons into peripheral nerve grafts.

Polysialylated Neural Cell Adhesion Molecule Is Necessary for Selective Targeting of Regenerating Motor Neurons

“…2 B). Although it is impossible to determine the source of the PSA via light microscopy, previous studies that used electron microscopy have shown that the vast majority of PSA reexpressed in regener-ating nerves is neural in origin (Zhang et al, 1995). Consequently, the dramatic upregulation of PSA in the muscle and cutaneous pathways most likely is attributable to the reexpression of PSA by regenerating axons and not to the synthesis of PSA by neighboring Schwann cells.…”

“…However, there are several lines of evidence to suggest that the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are involved. PSA and NCAM are both reexpressed by regenerating motor axons after peripheral nerve in-jury (Zhang et al, 1995;Rutishauser and Landmesser, 1996). During development motor axons must express PSA to innervate their appropriate muscle target(s) selectively (Tang et al, 1992(Tang et al, , 1994.…”

Neuritic Outgrowth Associated with Astroglial Phenotypic Changes Induced by Antisense Glial Fibrillary Acidic Protein (GFAP) mRNA in Injured Neuron–Astrocyte Cocultures

“…Laminin in its synthesis and its distribution therefore may be one of the factors that play a role in the lack of inhibition of neurite outgrowth after antisense treatment. Alternatively, one cannot exclude that, rather than an alteration-or a lack thereof-in the synthesis of secreted molecules, the maintained ability of reactive astrocytes to support axonal regrowth may be related to membrane-bound molecules involved in cell-to-cell contact between neurons and astrocytes, such as cell adhesion molecules (for review, see Zhang et al, 1995).…”

L1.1 Is Involved in Spinal Cord Regeneration in Adult Zebrafish

“…During peripheral nerve regeneration, L1 is expressed in motor neurons and Schwann cells (Martini and Schachner, 1988;Zhang et al, 2000). In the mammalian CNS, expression of L1 is increased in subpopulations of axotomized neurons only when their axons regrow into a permissive peripheral nerve graft (Zhang et al, 1995). Infusion of L1-Fc fusion protein into the lesioned adult rat spinal cord promotes locomotor recovery (Roonprapunt et al, 2003).…”