Early construction of the thalamocortical axon pathway requires c‐Jun N‐terminal kinase signaling within the ventral forebrain

Background Thalamocortical connectivity is essential for normal brain function. This important pathway is established during development, when thalamic axons extend a long distance through the forebrain before reaching the cerebral cortex. In this study, we identify a novel role for the c‐Jun N‐terminal kinase (JNK) signaling pathway in guiding thalamocortical axons through intermediate target territories. Results Complete genetic removal of JNK signaling from the Distal‐less 5/6 (Dlx5/6) domain in mice prevents thalamocortical axons from crossing the diencephalon‐telencephalon boundary (DTB) and the internal capsule fails to form. Ventral telencephalic cells critical for thalamocortical axon extensions including corridor and guidepost neurons are also disrupted. In addition, corticothalamic, striatonigral, and nigrostriatal axons fail to cross the DTB. Analyses of different JNK mutants demonstrate that thalamocortical axon pathfinding has a non‐autonomous requirement for JNK signaling. Conclusions We conclude that JNK signaling within the Dlx5/6 territory enables the construction of major axonal pathways in the developing forebrain. Further exploration of this intermediate axon guidance territory is needed to uncover mechanisms of axonal pathfinding during normal brain development and to elucidate how this vital process may be compromised in neurodevelopmental disorders. Key Findings Thalamocortical axons misroute at the diencephalic‐telencephalic boundary (DTB) in mice lacking JNK signaling in Distal‐less 5/6‐positive cells of the ventral forebrain. Intermediate targets of thalamocortical axon guidance including corridor cells, striatal axons, and ventral telencephalic guidepost neurons are disrupted in these mice. Corticothalamic, striatonigral, and nigrostriatal axon pathways are also misrouted and fail to cross the DTB in these mice.