The broad long-term goal of this application is to identify novel ligands for cell surface receptors, and to characterize their functions in vertebrate development, particularly development of neural connections.
Aim 1 focuses on identification of novel ligands. The first part of aim 1 deals with receptor-like protein tyrosine phosphatases of the mammalian LAR family. Previous genetic studies show functions for these molecules in neural development, but their actions and putative ligands are still not well understood. The second part of aim 1 deals with the Amyloid Precursor Protein (APP), which is cleaved to form the beta-amyloid peptide implicated in Alzheimer's disease. Despite its pathological relevance, the natural function of APP is not well understood. It has long been suggested that APP may function as a ligand or receptor, and in preliminary studies we have shown a novel-binding pattern to developing axons. Further studies are in progress to identify and characterize the ligand(s) responsible for this binding. Aim 2 proposes continued studies on developmental functions of the ephrins, a family of ligands identified during earlier cycles of the project. The focus is on experiments to elucidate novel principles of ephrin function, such as roles in coordinating cortical cell development, and roles at the synapse. Aim 3 is to study the functional roles of RNA-based regulation mechanisms in developmental axon guidance. Work by us and other groups has recently led to considerable interest in local protein translation and RNA-based control mechanisms in axon guidance. We are currently studying roles of novel RNA-based control mechanisms in growth cone steering, and in changes of axon responsiveness at intermediate targets such as the spinal cord midline
