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Previous Article | Next Article
The Journal of Neuroscience, February 15, 1998, 18(4):1240-1249
Acetylcholinesterase Enhances Neurite Growth and Synapse Development through Alternative Contributions of Its Hydrolytic Capacity, Core Protein, and Variable C Termini
Meira Sternfeld1, Guo-li Ming2, Hong-jun Song2, Keren Sela1, Rina Timberg1, Mu-ming Poo2 and Hermona Soreq1 1 Department of Biological Chemistry, The Life Sciences Institute, The Hebrew University of Jerusalem, 91904, Israel, and 2 Department of Biology, University of California at San Diego, La Jolla, California 92093-0357
Accumulated indirect evidence suggests nerve growth-promoting activities for acetylcholinesterase (AChE). To determine unequivocally whether such activities exist, whether they are related to the capacities of this enzyme to hydrolyze acetylcholine and enhance synapse development, and whether they are associated with alternative splicing variants of AChEmRNA, we used four recombinant human AChEDNA vectors. When Xenopus laevis embryos were injected with a vector expressing the synapse-characteristic human AChE-E6, which contains the exon 6-encoded C terminus, cultured spinal neurons expressing this enzyme grew threefold faster than co-cultured control neurons. Similar enhancement occurred in neurons expressing an insertion-inactivated human AChE-E6-IN protein, containing the same C terminus, and displaying indistinguishable immunochemical and electrophoretic migration properties from AChE-E6, but incapable of hydrolyzing acetylcholine. In contrast, the nonsynaptic secretory human AChE-I4, which contains the pseudointron 4-derived C terminus, did not affect neurite growth. Moreover, no growth promotion occurred in neurons expressing the catalytically active C-terminally truncated human AChE-E4, demonstrating a dominant role for the E6-derived C terminus in neurite extension. Also, AChE-E6 was the only active enzyme variant to be associated with Xenopus membranes. However, postsynaptic length measurements demonstrated that both AChE-E6 and AChE-E4 enhanced the development of neuromuscular junctions in vivo, unlike the catalytically inert AChE-E6-IN and the nonsynaptic AChE-I4. These findings demonstrate an evolutionarily conserved synaptogenic activity for AChE that depends on its hydrolytic capacity but not on its membrane association. Moreover, this synaptogenic effect differs from the growth-promoting activity of AChE, which is unrelated to its hydrolytic capacity yet depends on its exon 6-mediated membrane association.
Key words: acetylcholinesterase; alternative C termini; neurogenesis; neurite extension; noncatalytic function; Xenopus spinal neurons; synaptogenesis; neuromuscular junctions
Copyright © 1998 Society for Neuroscience 0270-6474/98/1841240-10$05.00/0
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