Single cell deletion of the transcription factors Sox9 and Trps1 reveals novel functions in adult cortical astrocytes [Spatial transcriptomics]

Astrocytes play key roles in brain function but it is still poorly understood how these are orchestrated by pan-astrocyte transcriptions factors (TFs). Here we examined the function of the well-known pan-astrocyte TF Sox9 and the novel astrocyte TF Trps1 (Transcriptional Repressor GATA Binding 1) by Cas9-mediated in vivo deletion using Mokola-pseudotyped lentiviral delivery into the adult cerebral cortex. The consequences of deleting either Sox9 or Trps1 alone or simultaneously were explored at single cell level (by patch-based single cell transcriptomics) and tissue level (by spatial transcriptomics). This revealed TF-specific functions in astrocytes, like synapse maintenance and immune response, as well as non-cell-autonomous effects on the surrounding cells such as on oligodendrocytes and other immune cells. Interestingly, deleting both factors cancels out some effects, suggesting that they antagonize each other’s function to some extent. Taken together, this study reveals a novel role of Trps1 and Sox9 in adult astrocytes and their communication with other glial and immune cells.