We have recently demonstrated that binding by monoclonal antibody (mAb) 8A2 to regenerating retinal ganglion cell axons in goldfish explants specifically induces a sustained, actin-based retraction response that is similar in most respects to a spontaneous retraction (S.G. Finnegan, V. Lemmon, and E. Koenig, Cell Motil. Cytoskeleton, 1992). Experiments were conducted to evaluate potential signal transduction pathways that may play a role in mediating retraction, using the mAb 8A2 retraction model system. Potential roles of cAMP, elevated intracellular calcium, or calmodulin-dependent processes were probed and the results did not appear to implicate them in either the induction or the maintenance of the axon retraction response. In contrast, treatment with phorbol 12-myristate 13-acetate, but not with inactive phorbol esters, induced a retraction response, although the response was more variable and less robust than that produced by mAb 8A2. However, both forms of induction were blocked by staurosporine, a nonspecific kinase inhibitor. Okadaic acid, a potent serine/threonine phosphatase inhibitor produced a very robust retraction response, and subthreshold doses significantly potentiated the retraction response induced by mAb 8A2. Genistein inhibited the mAb 8A2-induced retraction response at concentrations selective for tyrosine kinase activity in a dose-dependent manner. These findings are consistent with the hypothesis that an augmented phosphorylation state of one or more axonal proteins, perhaps catalyzed in part by protein kinase C, produces a sustained physiological retraction. In addition, tyrosine kinase may be involved in transducing surface-mediated interactions that trigger retraction, including the binding reaction signal of mAb 8A2.
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"but may imply that there are qualitative differences such as the involvement of different second messenger systems. In support of this idea, Finnegan and colleagues determined that collapse and retraction of goldfish retinal ganglion cell axons in response to monoclonal antibody 8A2 were not due to alteration of intracellular calcium concentration, but rather to elevated phosphorylation levels mediated by protein kinase C and a tyrosine kinase (Finnegan et al., 1993). Further studies on the proximal events in CAM-and integrin-mediated signals in growth cones are clearly required in order to understand the function of these molecules in axonal pathfinding. "
[Show abstract][Hide abstract] ABSTRACT: As axons advance to appropriate target tissues during development, their growth cones encounter a variety of cell adhesion molecules (CAMs) and extracellular matrix molecules (ECM molecules). Purified CAMs and ECM molecules influence neurite outgrowth in vitro and are thought to have a similar function in vivo. For example, when retinal ganglion cell (RGC) neurons are grown on different CAM and ECM molecule substrates in vitro, their growth cones display distinctive morphologies (Payne et al., 1992). Similarly, RGC growth cones in vivo have distinctive shapes at different points in the pathway from the eye to the tectum, suggesting the presence of localized cues that determine growth cone behaviors such as pathway selection at choice points. In this report, time-lapse video microscopy was utilized to examine dynamic transformations of RGC growth cones as they progressed from L1/8D9, N-cadherin, or laminin onto a different substrate. Contact made by the leading edge of a growth cone with a new substrate resulted in a rapid and dramatic alteration in growth cone morphology. In some cases, the changes encompassed the entire growth cone including those regions not in direct contact with the new substrate. In addition, the growth cones displayed a variety of behavioral responses that were dependent upon the order of substrate contact. These studies demonstrate that growth cones are actively affected by the substrate, and suggest that abrupt changes in the molecular composition of the growth cone environment are influential during axonal pathfinding.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/1995; 15(6):4370-81. · 6.34 Impact Factor
"CRYPα could be either antagonising the action of PTKs or, given the ability of R-PTPs CD45 and PTPα to activate src-family PTKs (Mustelin et al., 1989; Den et al., 1993), CRYPα could be having an agonistic effect on src-related PTKs of axons. Given the proposed role of PTKs in axonal growth, guidance, and retraction (Gertler et al., 1989; Bixby and Jhabvala, 1993; Finnegan et al., 1993; Miller et al., 1993; Smalheiser, 1993; Ignelzi et al., 1994; Williams et al., 1994c), it is not difficult to place this phosphatase into a regulatory scenario. As well as PTKs as potential axonal targets, one cytoskeletal target of phosphatases may be tubulin, the microtubule protein which is phosphorylated by pp60 c-src under the influence of CAMs (Matten et al., 1990; Atashi et al., 1992). "
[Show abstract][Hide abstract] ABSTRACT: Migrating embryonic growth cones require multiple, membrane-associated signalling molecules to monitor and respond to guidance cues. Here we present the first evidence that vertebrate cell adhesion molecule-like protein tyrosine phosphatases are likely to be components of this signalling system. CRYP alpha, the gene for an avian cell adhesion molecule-like phosphatase, is strongly expressed in the embryonic nervous system. In this study we have immunolocalised the protein in the early chick embryo and demonstrated its predominant localisation in axons of the central and peripheral nervous systems. This location suggests that the major, early role of the enzyme is in axonal development. In a study of sensory neurites in culture, we furthermore show that this phosphatase localises in migrating growth cones, within both the lamellipodia and filopodia. The dependence of growth cone migration on both cell adhesion and signalling through phosphotyrosine turnover, places the cell adhesion molecule-like CRYP alpha phosphatase in a position to be a regulator of these processes.
Development 07/1995; 121(6):1833-44. · 6.46 Impact Factor