Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction

Astrocytes in the brain exhibit regional heterogeneity contributing to regional circuits involved in higher-order brain functions, yet the mechanisms controlling their distribution remain unclear. Here, we show that the precise allocation of astrocytes to specific brain regions during development is achieved through transcription factor 4 (Tcf4)-mediated fate restriction based on their embryonic origin. Loss of Tcf4 in ventral telencephalic neural progenitor cells alters the fate of oligodendrocyte precursor cells to transient intermediate astrocyte precursor cells, resulting in mislocalized astrocytes in the dorsal neocortex. These ectopic astrocytes engage with neocortical neurons and acquire features reminiscent of dorsal neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during the differentiation of oligodendrocyte precursor cells derived from the ventral telencephalon, thereby restricting the fate to the oligodendrocyte lineage in the dorsal neocortex. Together, our findings highlight a previously unappreciated role for Tcf4 in regulating astrocyte allocation, offering additional insights into the mechanisms underlying neurodevelopmental disorders linked to Tcf4 mutations. Synopsis Astrocytes in the brain exhibit significant regional diversity, but the mechanisms controlling their heterogeneity remain unclear. This study demonstrates that transcription factor 4 (Tcf4) regulates astrocyte allocation to specific brain regions through fate restriction based on their embryonic origin. Loss of Tcf4 in the Nkx2.1 lineage results in ectopic astrocytes in the dorsal neocortex. Tcf4-deficient ectopic astrocytes with ventral origin can adapt to the local neocortical environment engaging with nearby neurons. Tcf4 suppresses the expression of genes related to astrocytogenesis in the Nkx2.1 lineage of the dorsal neocortex. Transcription factor Tcf4 confines precursor cell fate and determines regional astrocyte diversification during brain development.