The UNC5C Netrin Receptor Regulates Dorsal Guidance of Mouse Hindbrain Axons

The cerebellum receives its input from multiple precerebellar nuclei located in the brainstem and sends processed information to other brain structures via the deep cerebellar neurons. Guidance molecules that regulate the complex migrations of precerebellar neurons and the initial guidance of their leading processes have been identified. However, the molecules necessary for dorsal guidance of precerebellar axons to the developing cerebellum or for guidance of decussating axons of the deep nuclei are not known. To determine whetherUnc5cplays a role in the dorsal guidance of precerebellar and deep cerebellar axons, we studied axonal trajectories of these neurons inUnc5c−/−mice. Our results show thatUnc5cis expressed broadly in the precerebellar and deep cerebellar neurons.Unc5cdeletion disrupted long-range dorsal guidance of inferior olivary and pontine axons after crossing the midline. In addition, dorsal guidance of the axons from the medial deep cerebellar and external cuneate neurons was affected inUnc5c−/−mice, as were anterior migrations of pontine neurons. Coincident with the guidance defects of their axons, degeneration of neurons in the external cuneate nucleus and subdivisions of the inferior olivary nucleus was observed inUnc5c−/−mice. Lastly, transgenic expression ofUnc5cin deep neurons and pontine neurons by theAtoh1promoter rescued defects of the medial deep cerebellar and pontine axons observed inUnc5c−/−embryos, demonstrating thatUnc5cacts cell autonomously in the guidance of these axons. Our results suggest thatUnc5cplays a broad role in dorsal guidance of axons in the developing hindbrain.