The neuropathology observed in fetal alcohol syndrome (FAS) is strikingly similar to that observed in humans with mutations in the cell adhesion molecule L1. Since these L1 mutations are known to disrupt extracellular adhesion and some are presumed to block intracellular signaling, the effects of FAS may be due in part to disrupted LI adhesive signal transduction during development. During development cell adhesion molecules (CAMS) mediate many of the cell-cell interactions essential for appropriate axon pathfinding and synapse formation. In order for CAMS to do this, they are restricted to particular cell types, targeted to either axons or dendrites, and in many cases, to particular regions within axons and dendrites. Virtually nothing is known about how CAMS become targeted to particular cellular domains, how they are retained or for molecules of the Ig superfamily, how adhesive signals are transduced from the surface to the cytoskeleton. The overall goal of this proposal is to define intracellular sorting strategies and signaling pathways that are employed by the axonal CAM L1 and to determine whether these strategies are undermined by exposure to alcohol. To do this, we will identify the molecular domains required to mediate some of the functions of L1 so that ultimately we may identify signaling pathways that are disrupted by alcohol during critical developmental. periods.
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