Neocortical astrocyte diversity stems from distinct developmental origins

Abstract

Key regulators of neural network activity in multiple advanced cognitive processes and essential components of the blood-brain barrier, astrocytes constitute a highly heterogeneous population at the morphological, molecular, and functional levels. However, how this diversity arises during mammalian brain development remains poorly investigated. Here, using a combination of multicolour genetic fate mapping, single-cell transcriptomic analyses, multichannel large-volume imaging and detailed 3D cell morphology reconstructions, we uncover a discrete subpopulation of neocortical astrocytes generated from an early restricted embryonic domain located outside of the dorsal pallium. Besides their separate lineage from pyramidal neurons, these astrocytes exhibit a developmental trajectory that differs from astrocytes produced by dorsal cortical progenitors, including different migratory pathways, spatial distributions and morphology. Overall, our results reveal the diversity of embryonic sources responsible for neocortical astrocyte genesis and provide key insights into the unsuspected complex developmental processes that underlie cortical astrocyte heterogeneity.