Regulation of neuronal fate specification and connectivity of the thalamic reticular nucleus by the Ascl1-Isl1 transcriptional cascade

The thalamic reticular nucleus (TRN) is an anatomical and functional hub that modulates the flow of information between the cerebral cortex and thalamus, and its dysfunction has been linked to sensory disturbance and multiple behavioral disorders. Therefore, understanding how TRN neurons differentiate and establish connectivity is crucial to clarify the basics of TRN functions. Here, we showed that the regulatory cascade of the transcription factors Ascl1 and Isl1 promotes the fate of TRN neurons and concomitantly represses the fate of non-TRN prethalamic neurons. Furthermore, we found that this cascade is necessary for the correct development of the two main axonal connections, thalamo-cortical projections and prethalamo-thalamic projections. Notably, the disruption of prethalamo-thalamic axons can cause the pathfinding defects of thalamo-cortical axons in the thalamus. Finally, forced Isl1 expression can rescue disruption of cell fate specification and prethalamo-thalamic projections in in vitro primary cultures of Ascl1-deficient TRN neurons, indicating that Isl1 is an essential mediator of Ascl1 function in TRN development. Together, our findings provide insights into the molecular mechanisms for TRN neuron differentiation and circuit formation.