Functional redundancy of acetylcholinesterase and neuroligin in mammalian neuritogenesis.
Accumulated evidence attributes noncatalytic morphogenic activitie(s) to acetylcholinesterase (AChE). Despite sequence homologies, functional overlaps between AChE and catalytically inactive AChE-like cell surface adhesion proteins have been demonstrated only for the Drosophila protein neurotactin. Furthermore, no mechanism had been proposed to enable signal transduction by AChE, an extracellular enzyme. Here, we report impaired neurite outgrowth and loss of neurexin Ialpha mRNA under antisense suppression of AChE in PC12 cells (AS-ACHE cells). Neurite growth was partially rescued by addition of recombinant AChE to the solid substrate or by transfection with various catalytically active and inactive AChE variants. Moreover, overexpression of the homologous neurexin I ligand, neuroligin-1, restored both neurite extension and expression of neurexin Ialpha. Differential PCR display revealed expression of a novel gene, nitzin, in AS-ACHE cells. Nitzin displays 42% homology 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 redundant neurite growth-promoting activities for AChE and neuroligin and implicate interactions of AChE-like proteins and neurexins as potential mediators of cytoarchitectural changes supporting neuritogenesis.
Grifman
M
M
Department of Biological Chemistry, Institute of Life Sciences, Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Galyam
N
N
Seidman
S
S
Soreq
H
H
D000110:Acetylcholinesterase / Q000494:pharmacology / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal; D018014:Gene Transfer Techniques; D006023:Glycoproteins; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure*; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats
D015816:Cell Adhesion Molecules, Neuronal; D006023:Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense; C112162:neurexophilin; C093438:neuroligin 1; D000110:Acetylcholinesterase