Topographic specification of thalamocortical projectionrole of lhx2 transcription factor and target cells at the ventral telencephalon

Resumen

In my PhD Thesis, we studied the thalamocortical axonal track development at early stages in mouse embryogenesis, and we found that both the migration of a subpopulation of interneurons at the subpallium and the guidance and topography of thalamocortical axons (TCAs) is mediated by Robo/Slit signaling. Moreover, the three studies included here are clearly interrelated. First, we demonstrated that the mechanism by which the migration of ¿corridor-like cells¿ occurs at the ventral telencephalon relays of Slit/Robo signaling and is the responsible for major changes in corridor cell positioning and thalamocortical axonal trajectories. Second, once these cells are settled, they express gradients of guidance cues that act in combination to topographically sort thalamocortical axons. This combination of guidance cues requires the expression of Slit and Robo receptors in TCAs. Finally, we decipher an upstream transcription factor that regulates the expression of Robo1 and Robo2 receptors in TCAs. The transcription factor Lhx2, is dynamically regulated in distinct populations of thalamic neurons and thus allows a differential expression of Robo1 and Robo2 receptors in specific sets of TCAs. Corridor cell migration begins at very early stages, around the embryonic stage E12, to be settled in the moment in which the TCAs cross the ventral telencephalon (E13), since they form a permissive axonal bridge in an otherwise non-permissive environment. The initial steps of their migration arise through Slit/Robo signalling that allows a strong repulsion from the proliferative areas that also has a role in positioning corridor cells in specific regions of the MGE mantle. At the time that TCAs begin to grow from the thalamus, they also activate their transcriptional machinery to express the guidance receptors required to feel the signals presented by corridor cells. Interestingly, the same molecules, that previously were responsible for corridor cells positioning, also guide rostral and intermediate TCAs to their targets. Thus, Robo receptors expression in TCAs allow them to read the gradients of Slit1 and Netrin 1 necessary for the rostro-caudal axonal sorting to specific cortical areas. Lastly, we found that the Lhx2 transcription factor regulates Robo receptors expression at the moment in which TCAs begin to navigate. The fact that Lhx2 is a repressor of Robo receptors expression fits very well with our model because rostral and intermediate axons express very low levels of Lhx2 at the time of axonal pathfinding. Therefore, the expression of Robo receptors will be high in these axons and thus will allow a correct interaction with Netrin 1 receptors and trigger the combinatorial activity described. By contrary, Lhx2, which is mainly expressed at medial and caudal levels, and more specifically in the MGv cells will allow low levels of Robo expression to target the auditory cortical area present at caudo-lateral regions of the cortex. In sum, our study provide a nice recompilation of data that shows how the brain has develop the reuse of strategies and axon guidance molecules to allow a major axonal tract to develop.