RESPONSE OF RETINAL GANGLION-CELL AXONS TO STRIPED LINEAR GRADIENTS OF REPELLENT GUIDANCE MOLECULES

Although molecular gradients have long been postulated to play a role in the development of topographic projections in the nervous system, r elatively little is known about how axons evaluate gradients. Do growt h cones respond to concentration or to slope? Do they react suddenly o r gradually? Is there adaptation? In the developing retinotectal syste m, temporal retinal ganglion cell axons have previously been shown to avoid repellent cell-surface activities distributed in gradients acros s the optic tectum. We confronted temporal retinal axons with precisel y formed striped linear gradients of repellent tectal membranes and of two candidate repellent molecules, ephrin-A2 and -A5. Axons entered g radient stripes independently of their slope and extended unhindered i n the uphill direction until they suddenly avoided an apparent thresho ld concentration of repellent material that was independent of slope. This: critical concentration was similar in both linear and nonlinear gradients, and hence independent of gradient shape. When gradients of identical slope were formed on different basal levels of repellent mat erial, axons grew uphill for a fixed increment of concentration, possi bly measured from the lowest point of the gradient, rather than up to a fixed absolute concentration. The speed of growth cones was not affe cted by repellent unstriped gradients below the critical concentration level. Similar results were found with membranes from cell lines stab ly transfected with either ephrin-A5 or ephrin-A2, two previously iden tified growth cone repellent cell-surface proteins. These data suggest that growth cones or axons can integrate guidance information over la rge distances, probably by a combined memory and adaptation mechanism, (C) 1998 John Wiley & Sons, Inc.