9727971 MACAGNO Despite many novel recent findings, it is still a mystery how cells in the developing nervous system know where to grow. Most neurons, by the time they have reached maturity, have elaborated long projections (axons) that follow set pathways to reach targets far from their cell bodies. To do this, they must make a myriad of choices, such as when and where to grow, where to turn, and how to stop growing when they reach the correct target. These phenomena are thought to be mediated by the growth cone, a specialized motile structure found at the leading edge of the growing axon. Growth cones are believed to posses a variety of molecular receptors on their surface membranes that sense and relay into the cell local environmental signals as they are encountered, which then induce the cell to make steering and growth decisions. Dr. Eduardo Macagno and his collaborators will study how a pair of newly-described molecular receptors, known as LAR-like receptor tyrosine phosphatases, are involved in axon growth and in target selection. The structure of these molecules suggests that their domains outside the cell can bind specific molecules and that such binding could activate their domains inside the cell, which can in turn modify the properties of other components of the cell machinery. Preliminary experimental results have suggested that these molecular receptors play important roles in the decisions of where and perhaps when certain neurons will grow. Using the embryonic leech as a simplified system in which to study the process of axon outgrowth, it was demonstrated that when the normal functioning of these receptors is interfered with, the neurons that normally express these receptors often undergo strongly aberrant patterns of growth. Dr. Macagno's research group will be examining in more detail what roles these receptors play in normal neuronal development. For example, do they help decide where and when branches turn, or how fast they grow? To help answer suc h questions, observations will be made over time on live, individual neurons, as their axonal projections extend in the developing embryo. They will also use both genetic and biochemical approaches to identify the molecules that bind to these receptors, determine where such molecules are located in the developing embryo, and study what happens in the growth cone when they bind to the receptors. Results from these studies will help elucidate the nature of the molecular receptor-based signaling processes that occur in growth cones, and thus help us to understand how neurons find and recognize their targets in the developing animal.
