Ethanol inhibits L1-mediated neurite outgrowth in postnatal rat cerebellar granule cells.
The neuropathology of the effects of ethanol on the developing central nervous system are similar to those of patients with mutations in L1, a neural cell adhesion molecule. This observation suggests that inhibition of L1 plays a role in the pathogenesis of alcohol-related neurodevelopmental disorders. Here we examine the effects of ethanol on L1 homophilic binding and on L1-mediated neurite outgrowth. Ethanol had no effect on cell adhesion or aggregation in a myeloma cell line expressing full-length human L1. In contrast, the rate of L1-mediated neurite outgrowth of rat postnatal day 6 cerebellar granule cells grown on a substratum of NgCAM, the chick homologue of L1, was inhibited by 48.6% in the presence of ethanol with a half-maximal concentration of 4.7 mM. The same effect was found with soluble L1-Fc, thus showing that the inhibitory effect is not dependent on cell adhesion. In contrast, neither laminin nor N-cadherin-mediated neurite outgrowth was inhibited by physiologic concentrations of ethanol. We conclude that one mechanism of ethanol's toxicity to the developing central nervous system may be the inhibition of L1-mediated neurite outgrowth.
Bearer
C F
CF
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. cfb3@po.cwru.edu
Swick
A R
AR
O'Riordan
M A
MA
Cheng
G
G
D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D016501:Neurites / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014407:Tumor Cells, Cultured
D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D000431:Ethanol