Abstract. Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. Ll-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited Ll-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. Ll-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit Ll-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of Ll-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of Ll-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders. FETAL alcohol syndrome (FAS) 1 is one of the most common recognizable syndromes associated with mental retardation in the Western world (1). The full syndrome, characterized by growth retardation, neurological abnormalities, and facial malformations, occurs in N5% of the offspring of alcoholic women (1, 72). Neuropathological examination and neuroimaging of children with FAS have disclosed a spectrum of neurodevelopmental abnormalities, including hydrocephalus, agenesis of the corpus callosum, neuronal-glial heterotopias, cerebellar dysplasia, and microcephaly (8,27,62). Some of these lesions arise from disordered migration of neural cells, which has also been demonstrated experimentally in animal models of FAS (45,46 X-linked syndrome associated with mutations in the gene encoding L1, an immunoglobulin cell adhesion molecule (IgCAM) (4,20,28,31,66,74,83). Three overlapping syndromes, X-linked hydrocephalus, MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and X-linked complicated spastic paraplegia, were each mapped to the same region (Xq28) of the X chromosome (32,76,82). A large number of different missense mutations, short deletions, and defects of alternative splicing within the L1 gene have been identified in individuals with these X-linked disorders (83); similar mutations have never been encountered in large numbers of control subjects. A single point mutation in L1 can cause either X-linked hydro...

No abstract

Ceruloplasmin is a key enzyme involved in detoxifying ferrous iron, which can generate free radicals. The secreted form of ceruloplasmin is produced by the liver and is abundant in serum. We have previously identified a membrane-bound glycosylphosphatidylinositol (GPI)-anchored form of ceruloplasmin (GPI-Cp) that is expressed by astrocytes in the central nervous system (CNS) (Patel and David. 1997. J Biol Chem 272:20185-20190). We now provide direct evidence that rat leptomeningeal cells, which cover the surface of the brain, also express GPI-Cp. The expression of GPI-Cp on the surface of these cells increases with postnatal development and is regulated in vitro by cell density, time in culture, and various extracellular matrix molecules. The expression of GPI-Cp also appears to be regulated differently in astrocytes and leptomeningeal cells in vitro. The abundant expression of GPI-Cp on the surface of leptomeningeal cells suggests that these cells play a role in antioxidant defense along the surface of the postnatal CNS possibly by detoxifying the cerebrospinal fluid.

No abstract