Early construction of the thalamocortical axon pathway requires JNK signaling within the ventral forebrain

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. 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 extension 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 demonstrates that thalamocortical axon pathfinding has a non-autonomous requirement for JNK signaling. We conclude that JNK signaling within the Dlx5/6 territory enables the construction of major axonal pathways in the developing forebrain. Impact statement We find an obligate, non-autonomous requirement for JNK signaling in early thalamocortical axon pathfinding, providing new mechanistic insight into the establishment of axonal connections in the developing forebrain.