Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway

In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and in postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss of Foxg1 in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway component Fgfr3, that is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic ligand FGF18 in newborn neocortical upper-layer neurons. Loss of FOXG1 in postmitotic neurons increases Fgf18 expression and enhances gliogenesis in the progenitors. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated in Foxg1 null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex. To assess the implications of the loss of Foxg1 in the neuron-glia cell fate decisions in the developing cerebral cortex, hGFAPCreERT2; Foxg1lox/lox; Ai9 (Progenitor Control) mice were administered Tamoxifen at E15.5 to delete Foxg1 from the progenitors. Brains were isolated, and the fluorescently labelled mutant cells were FACS-purified at E17.5. The corresponding Controls were obtained by administering FlashTag at E15.5 in WT brains and FACS purifying the cells at E17.5. For postmitotic neuron-specific deletion of Foxg1, cortical plate were collected at P1 from NexCre/+; Foxg1lox/lox; FR/FRT (postmitotic mutant) or their littermate controls Foxg1lox/lox; FRT/FRT.