In bilaterally symmetric organisms, the midline is a critical organizing center for the developing central nervous system. There is a striking conservation of the molecules and mechanisms that control axon path finding at the midline in vertebrate and invertebrate nervous systems. The majority of axons in the CNS cross the midline before projecting to their contralateral synaptic targets and this crossing decision is under exquisite spatial and temporal regulation. Growing commissural axons initially respond to attractive signals, while inhibiting responses to repulsive signals. Once across, repulsion dominates, allowing axons to leave and preventing them from re-entering the midline. Here we review recent advances in flies and mice that illuminate the molecular mechanisms underlying the establishment of precise connectivity at the midline.
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