Target selection by cortical axons: Alternative mechanisms to establish axonal connections in the developing brain

We have described our studies of the development of projections from layer 5 of the rat neocortex to subcortical targets in the midbrain and hindbrain. The major points are briefly summarized here. 1. Layer-5 neurons extend a primary axon out of cortex and along a spinally directed trajectory, bypassing all of their targets in the midbrain and hindbrain. These targets are later contacted exclusively by collaterals formed by a delayed interstitial branching of the primary axon, not by growth cone bifurcation. 2. Collateral branches only form at stereotypic positions, not randomly along the length of the axon. Thus, specific cues identify branch points, and the length of the primary axon well behind its growth cone responds to these cues. 3. Layer-5 neurons in diverse areas of cortex initially develop the same basic set of collateral branches, although they will permanently retain different subsets of the initial common set. Therefore, branch cues are recognized by layer-5 neurons independent of whether the collateral projection formed is functionally appropriate for the cortical region in which the neuron resides. 4. In vitro and in vivo evidence indicates that one of the major branches, which forms the corticopontine projection, is induced and directed into its target, the basilar pons, by a diffusible, target-derived, tropic signal. Thus, a chemotropic cue promotes recognition of the basilar pontine target by the primary layer-5 axons. 5. In this system, then, target selection is not the responsibility of the growth cone of the primary axon. On the basis of morphological changes and growth trajectory of the growth cones of primary layer-5 axons, we conclude that their major role is to direct the axons out of cortex and maintain an undeviated growth down a single, common path.