Transient Neuronal Populations Are Required to Guide Callosal Axons: A Role for Semaphorin 3C

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Abstract
The corpus callosum (CC) is the main pathway responsible for interhemispheric communication. CC agenesis is associated with numerous human pathologies, suggesting that a range of developmental defects can result in abnormalities in this structure. Midline glial cells are known to play a role in CC development, but we here show that two transient populations of midline neurons also make major contributions to the formation of this commissure. We report that these two neuronal populations enter the CC midline prior to the arrival of callosal pioneer axons. Using a combination of mutant analysis and in vitro assays, we demonstrate that CC neurons are necessary for normal callosal axon navigation. They exert an attractive influence on callosal axons, in part via Semaphorin 3C and its receptor Neuropilin-1. By revealing a novel and essential role for these neuronal populations in the pathfinding of a major cerebral commissure, our study brings new perspectives to pathophysiological mechanisms altering CC formation. The largest commissural tract in the human brain is the corpus callosum, with over 200 million callosal axons that channel information between the two cerebral hemispheres. Failure of the corpus callosum to form appropriately is observed in several human pathologies and can result from defects during different steps of development, including cell proliferation, cell migration, or axonal guidance. Studies to date suggest that glial cells are critical for the formation of the corpus callosum. In this study, we show that during embryonic development, the corpus callosum, which was considered a neuron-poor structure, is in fact transiently populated by numerous glutamatergic and GABAergic neurons. With the use of in vitro graft experiments and of various transgenic mice, we demonstrate that neurons of the corpus callosum are essential for the accurate navigation of callosal axons. Moreover, we discovered that the guidance factor Semaphorin 3C, which is expressed by corpus callosum neurons, acts through the neuropilin 1 receptor to orient axons crossing through the corpus callosum. The present work therefore gives new insights into the mechanisms involved in axon guidance and implies that transient neurons work together with their glial partners in guiding callosal axons.