Molecular gradients and development of retinotopic maps.

Gradients of axon guidance molecules have long been postulated to control the development of the organization of neural connections into topographic maps. We review progress in identifying molecules required for mapping and the mechanisms by which they act, focusing on the visual system, the predominant model for map development. The Eph family of receptor tyrosine kinases and their ligands, the ephrins, remain the only molecules that meet all criteria for graded topographic guidance molecules, although others fulfill some criteria. Recent reports further define their modes of action and new roles for them, including EphB/ephrin-B control of dorsal-ventral mapping, bidirectional signaling of EphAs/ephrin-As, bifunctional action of ephrins as attractants or repellents in a context-dependent manner, and complex interactions between multiple guidance molecules. In addition, spontaneous patterned neural activity has recently been shown to be required for map refinement during a brief critical period. We speculate on additional activities required for map development and suggest a synthesis of molecular and cellular mechanisms within the context of the complexities of map development.