ALCOHOL EFFECTS ON GANGLIOSIDE DEPENDENT NEUROGENESIS

神经新生支配着发育性迁移、轴突和树突

Neuritogenesis governs developmental migration, axonogenesis and dendritic arborization of neurons, CNS phenomena which are aberrant in: experimental FAS. Neuritogenesis depends mechanistically upon l) plasma membrane- substratum adhesion and 2) neurital plasma membrane extension. The simple gangliosides GM3 and GD3 promote plasma membrane integrin-regulated and carbohydrate shear-modulated substrate adhesion. Synthesis of GM3/GD3 by IC-Golgi derived exofacial (ecto) sialyl transferases relocated within EGF-induced recycling endosomes, which are formed by EGF-induced endocytosis, may be a unique neuronal mechanism for promoting adhesion, by producing targeted localization of plasma membrane GM3/GD3. Chronic exposure of cells to ethanol reduces EGF-receptor (EGFR) endocytosis, thus limiting endosomal GM3/GD3 re-tailoring, and weakening adhesion loci. The effects of chronic ethanol exposure on GM3/GD3 sialylation in EGFR-induced endosomes will be quantitated in both a chick neuron culture and in an in ovo FAS model. Neurite plasma membrane extension requires addition to the plasma membrane of Golgi-derived plasma membrane elements with a very high structural content of neuritogenic (terminally-sialylated gangliotetraosyl ceramide) ganglioside glycoforms, particularly the major gangliosides GT1b, GQ1b Attenuated neuritogenesis results from inhibition of cytoskeletally regulated anterograde Golgi biosynthesis of GT1B, GQ1b. Dose-and time- dependent chronic ethanol-induced inhibition of biosynthesis of these gangliosides in neuron culture and a parallel whole embryo in ovo FAS model will be traced with [3H)ManNAc, as an obligate sialic acid precursor. Vulnerability of the differentiating embryonic CNS neuron to chronic ethanol-induced biosynthetic inhibition of sialylation of key neuronal gangliosides will be documented in detail. Evaluation will be made of exogenous re-supply of the neurital plasma membrane with building black gangliosides (GT1b/GQ1b) in neurite preservation A) in neuron culture and B) in vivo in embryonic chick brain, during chronic exposure to ethanol.