Pathfinding of Corticothalamic Axons Relies on a Rendezvous with Thalamic Projections

Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical... Full description

Major outputs of the neocortex are conveyed by corticothalamic axons (CTAs), which form reciprocal connections with thalamocortical axons, and corticosubcerebral axons (CSAs) headed to more caudal parts of the nervous system. Previous findings establish that transcriptional programs define cortical neuron identity and suggest that CTAs and thalamic axons may guide each other, but the mechanisms governing CTA versus CSA pathfinding remain elusive. Here, we show that thalamocortical axons are required to guide pioneer CTAs away from a default CSA-like trajectory. This process relies on a hold in the progression of cortical axons, or waiting period, during which thalamic projections navigate toward cortical axons. At the molecular level, Sema3E/PlexinD1 signaling in pioneer cortical neurons mediates a “waiting signal” required to orchestrate the mandatory meeting with reciprocal thalamic axons. Our study reveals that temporal control of axonal progression contributes to spatial pathfinding of cortical projections and opens perspectives on brain wiring. ► Corticothalamic and corticosubcerebral axons follow distinct subpallial trajectories ► Thalamic projections guide corticothalamic axons ► Meeting with thalamic axons relies on a waiting period of pioneer cortical axons ► PlexinD1/Sema3E signaling controls the waiting period Reciprocal connections between the thalamus and neocortex are established during development. Deck et al. show that the pathfinding of corticothalamic projections relies on an encounter with reciprocal thalamocortical axons. This encounter is timely controlled by PlexinD1/Sema3E signaling.