A Morphogenic Role for Acetylcholinesterase in Neurite Outgrowth

Abstract

During the past ten years there has been increasing interest in non-cholinergic roles for acetylcholinesterase (AChE) during neural development (1–3), specifically its role in axonal outgrowth. Building on descriptive data in developing chick (4–6), rat (7–10) and primate (11) nervous systems, our laboratory and others are providing a more direct link between AChE expression and process outgrowth through the use of in vitro systems. We have previously shown that non-cholinergic, rat dorsal root ganglion (DRG) neurons, express AChE and that the level of AChE increases in parallel with neurite outgrowth in culture (12–14). We have also shown that treatment with certain AChE inhibitors produces a dose-dependent, but reversible, reduction in outgrowth which is accompanied by altered neurite morphology and abnormal accumulations of neurofilaments in the cell body (12–14). Similar effects on outgrowth have also been obtained for other PNS (15) and CNS neurons (16–18). Overexpression of AChE has been shown to induce process growth (19–21) and conversely, treatment with AChE antisense oligodeoxynucleotides results in reduced neuritic outgrowth (20,22). While a mechanism underlying the morphogenic function of AChE has yet to be defined, these data are consistent with a cell adhesive role for AChE. This hypothesis, originally proposed by Layer et al., (17) is supported by data showing that AChE shares amino acid sequence homology with known cell adhesion molecules. In this regard, we have previously shown that the level of AChE expression is higher when DRG neurons are grown on substrata which are less permissive to outgrowth (23), suggestive of a role in cell-substratum interactions. In this report we review our studies demonstrating the effects of AChE monoclonal antibody treatment on both neurite outgrowth and attachment in primary cultures of DRG neurons (24). We also examine the effects on neuronal attachment when the culture substratum is supplemented with exogenous AChE. Finally, we propose potential adhesive mechanisms by which AChE may function in a morphogenic role.