Calcium release-dependent actin flow in the leading process mediates axophilic migration

Proper assembly of neural circuits requires newly born neurons to migrate from their place of origin to their final location. Little is known about the mechanisms of axophilic neuronal migration, whereby neurons travel along axon pathways to navigate to their destinations. Gonadotropin-releasing hormone (GnRH)-expressing neurons migrate along olfactory axons from the nose into the forebrain during development, and were used as a model of axophilic migration. After migrating, GnRH neurons are located in the hypothalamus and are essential for puberty and maintenance of reproductive function. To gain a better understanding of the mechanisms underlying axophilic migration, we investigated in mice the regulation of movement from calcium signals to cytoskeletal dynamics. Live imaging revealed robust calcium activity during axophilic migration, and calcium release through IP3 receptors was found to stimulate migration. This occurred through a signaling pathway involving the calcium sensor calcium/calmodulin protein kinase kinase, AMP-activated kinase, and RhoA/ROCK. By imaging GnRH neurons expressing actin-GFP or Lifeact-RFP, calcium release was found to stimulate leading process actin flow away from the cell body. In contrast, actin contractions at the cell rear were unaffected by this calcium signaling pathway. These findings are the first to test the regulation of cytoskeletal dynamics in axophilic migration, and reveal mechanisms of movement that have broad implications for the migration of other CNS populations.