Netrin-1 promotes thalamic axon growth and is required for proper development of the thalamocortical projection

The thalamocortical axon (TCA) projection originates in dorsal thalamus, co nveys sensory input to the neocortex, and has a critical role in cortical d evelopment. We show that the secreted axon guidance molecule netrin-1 acts in vitro as an attractant and growth promoter for dorsal thalamic axons and is required for the proper development of the TCA projection in vivo. As T CAs approach the hypothalamus, they turn laterally into the ventral telence phalon and extend toward the cortex through a population of netrin-1-expres sing cells. DCC and neogenin, receptors implicated in mediating the attract ant effects of netrin-1, are expressed in dorsal thalamus, whereas unc5h2 a nd unc5h3, netrin-1 receptors implicated in repulsion, are not. In vitro, d orsal thalamic axons show biased growth toward a source of netrin-1, which can be abolished by netrin-1-blocking antibodies. Netrin-1 also enhances ov erall axon outgrowth from explants of dorsal thalamus. The biased growth of dorsal thalamic axons toward the internal capsule zone of ventral telencep halic explants is attenuated, but not significantly, by netrin-1-blocking a ntibodies, suggesting that it releases another attractant activity for TCAs in addition to netrin-1. Analyses of netrin-1 -/- mice reveal that the TCA projection through the ventral telencephalon is disorganized, their pathwa y is abnormally restricted, and fewer dorsal thalamic axons reach cortex. T hese findings demonstrate that netrin-1 promotes the growth of TCAs through the ventral telencephalon and cooperates with other guidance cues to contr ol their pathfinding from dorsal thalamus to cortex.