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

Abstract

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.

Gli2-Mediated Shh Signaling Is Required for Thalamocortical Projection Guidance

“…This conclusion is also supported by the analysis of the TCAs trajectory in Pax6 -KO mice in which their axons are able to reach the hypothalamic territory due to a strong reduction in their levels of Robo2 in the thalamic neurons ( Clegg et al, 2015 ). A similar result has been recently described by the loss of c-Jun N-terminal kinase (JNK) signaling in the Dlx5/6 territory, the TCAs axons enter in the hypothalamic due to a total failure of the guidance cues and guideposts ( Cunningham et al, 2021 ).…”