FUNCTIONAL REDUNDANCY OF ACETYLCHOLINESTERASE AND NEUROLIGIN IN MAMMALIAN NEURITOGENESIS

Accumulated evidence attributes noncatalytic morphogenic activitie(s) to acetylcholinesterase (AChE), Despite sequence homologies, functiona l overlaps between AChE and catalytically inactive AChE-like cell surf ace adhesion proteins have been demonstrated only for the Drosophila p rotein neurotactin, Furthermore, no mechanism had been proposed to ena ble signal transduction by AChE, an extracellular enzyme. Here, we rep ort impaired neurite outgrowth and loss of neurexin I alpha mRNA under antisense suppression of AChE in PC12 cells (AS-ACHE cells). Neurite growth was partially rescued by addition of recombinant AChE to the so lid substrate or by transfection with various catalytically active and inactive AChE variants. Moreover, overexpression of the homologous ne urexin I ligand, neuroligin-1, restored both neurite extension and exp ression of neurexin I alpha. Differential PCR display revealed express ion of a novel gene, nitzin, in AS-ACHE cells. Nitzin displays 42% hom ology to the band 4.1 protein superfamily capable of linking integral membrane proteins to the cytoskeleton. Nitzin mRNA is high throughout the developing nervous system, is partially colocalized with AChE, and increases in rescued AS-ACHE cells. Our findings demonstrate redundan t neurite growth-promoting activities for AChE and neuroligin and impl icate interactions of AChE-like proteins and neurexins as potential me diators of cytoarchitectural changes supporting neuritogenesis.