Clonal lineage determines the direct conversion of thalamic astrocytes into subtype-specific thalamocortical neurons

Forced expression of defined transcription factors leads to the direct conversion of various cell types into induced neurons (iNs). Specifically, successful reprogramming of resident brain astrocytes in vitro as well as in vivo represents a great advantage for the generation of neurons and derived circuits. However, whether astrocytes from distinct brain regions might show a reprogramming specificity towards a unique iN type remains largely unknown. Here, we use direct reprogramming of thalamic astrocytes by Neurog2 to generate specific excitatory sensory-modality thalamocortical neurons. Moreover, we show that the origin, but not the environment of the astrocytes determines the fate of the iNs after direct reprogramming. Indeed, clonal analysis in the thalamus shows that astrocytes from the distinct thalamic nuclei are clonally related determining the specificity of the iNs generated from those astrocytes. We also found that the potential of the same transcription factor to reprogram nuclei-specific thalamic astrocytes into precise subsets of thalamocortical neurons depends on particular epigenetic modifications. In sum, our study provides novel insights into the mechanisms that control the specification of thalamic neurons and importantly those that are required for direct programming of sensory neurons. Generation of specific sensory brain circuits might be an approach for future rehabilitation strategies.