DIRECTED GROWTH OF EARLY CORTICAL AXONS IS INFLUENCED BY A CHEMOATTRACTANT RELEASED FROM AN INTERMEDIATE TARGET

Projection neurons throughout the mature mammalian neocortex extend ef ferent axons either through the ventrolaterally positioned internal ca psule to subcortical targets or through the dorsally located midline c orpus callosum to the contralateral cortex. In rats, the internal caps ule is pioneered on E14, but the corpus callosum is not pioneered unti l E17, even though these two types of projection neurons are generated at the same time. Here we use axonal markers to demonstrate that earl y cortical axon growth is directed toward the nascent internal capsule , which could account for the timing difference in the development of the two efferent pathways, This directed axon growth may be due to a c hemoattractant and/or a chemorepellent secreted by intermediate target s of corlical efferent axons, the nascent internal capsule, or the med ial wall of the dorsal telencephalon (MDT), respectively, To test for these soluble activities, explants of E15 rat neocortex and intermedia te targets were cocultured in collagen gels. Cortical axon outgrowth w as directed toward the internal capsule, but outgrowth was nondirected and suppressed when cocultured with MDT, suggesting that the internal capsule releases a chemoattractant for cortical axons, whereas the MD T releases a chemosuppressant. Because the chemoattractant Netrin-1 is expressed in the internal capsule, we cocultured cortical explants wi th E13 rat floor plate, which expresses Netrin-1, or with Netrin-1-tra nsfected or control-transfected 293T cells. Cortical axon growth was d irected toward both floor plate and Netrin-1-transfected 293T cells, a s it had been toward the internal capsule, but not toward control-tran sfected 293T cells. These findings suggest that early events in cortic al axon pathfinding may be controlled by a soluble activity which attr acts initial axon growth toward the internal capsule and that this act ivity may be due to Netrin-1.