Abstract
The corpus callosum (CC) is the largest fiber tract in the mammalian brain, linking the bilateral cerebral hemispheres. CC development depends on the proper balance of axon growth cone attractive and repellent cues leading axons to the midline and then directing them to the contralateral hemisphere. Imbalance of these cues results in CC agenesis or dysgenesis. Nogo receptors (NgR1, NgR2, and NgR3) are growth cone directive molecules known for inhibiting axon regeneration after injury. We report that mice lacking Nogo receptors (NgR123-null mice) display complete CC agenesis due to axon misdirection evidenced by ectopic axons including cortical Probst bundles. Because glia and glial-derived growth cone repellent factors (especially the diffusible factor Slit2) are required for CC development, their distribution was studied. Compared with wild-type mice, NgR123-null mice had a sharp increase in the glial marker glial fibrillary acidic protein (GFAP) and in Slit2 at the glial wedge and indusium griseum, midline structures required for CC formation. NgR123-null mice displayed reduced motor coordination and hyperactivity. These data are consistent with the hypotheses that Nogo receptors are membrane-bound growth cone repellent factors required for migration of axons across the midline at the CC, and that their absence results directly or indirectly in midline gliosis, increased Slit2, and complete CC agenesis. J. Comp. Neurol. 525:291-301, 2017. © 2016 Wiley Periodicals, Inc.