The long-term goal of this proposal is to understand how cell adhesion molecules (CAMs) integrate extracellular cues with the cytoskeleton and intracellular signaling pathways to carry out their roles. An important class of CAMs is the L1 family (L1CAMs), a set of immunoglobulin transmembrane glycoproteins that has been associated with several congenital X-linked neurological disorders. Although also expressed outside the nervous system, non-neuronal L1 CAM roles are not well characterized. L1CAMs are subjected to tyrosine phosphorylation, the in vivo implications of which are not known. The objectives of this research are to identify both neuronal and non-neuronal L1CAM functions as well as dissect the mechanisms by which L1CAMs carry out their roles in C. elegans. Three main aims are proposed to obtain these objectives. The primary goal in aim #1 is to identify the functions of the C. elegans L1CAM homologue, lad-l. Genetic lad-1 mutants, which exhibit both neuronal and non-neuronal phenotypes, will be examined to determine specific defects. We will also initiate a study of lad-2, a non-canonical L1 CAM, which was recently identified in C. elegans. The objective in aim#2 is to test if conserved domains in the L1 CAM cytoplasmic tail are functionally important in vivo via a structure-function analysis. We will focus on domains that include the ankyrin-binding motif, tyrosine-phosphorylation sites, and a PDZ-binding domain. We will also use a genetic approach to characterize two PDZ proteins we identified as LAD-1 interactors to determine if and how they regulate LAD-1 function. We also determined that the egl-15 FGFR and let-60 Ras signaling pathway is required for LAD-1 phosphorylation. The goal of Aim#3 is to determine genetically how phosphorylation by the FGFR-Ras signaling pathway regulates LAD-1 function. Achieving the aims of this proposal will allow us to better understand how LICAMs mediate their functions. This in turn, will help us in genetic therapy development for L1CAM-related neurological disorders.
