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 , which 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 new born 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 new born 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. Significance Statement Functional brain circuitry requires the correct numbers and subtypes of neurons and glia. A fundamental feature of the vertebrate central nervous system is that common progenitors produce first neurons and then glia. Cell-intrinsic factors modulate how a progenitor responds to cell-extrinsic cues to achieve this transition. Here, we report that the transcription factor Forkhead Box G1 ( Foxg1 ) regulates gliogenesis in the mouse neocortex in vivo by regulating different aspects of the gliogenic FGF signalling pathway in progenitors and in postmitotic neurons. Loss of Foxg1 results in premature gliogenesis via regulation of novel targets Fgfr3 in progenitors and Fgf18 in postmitotic neurons. Our findings offer mechanistic insight into FOXG1 syndrome, an Autism Spectrum Disorder caused by Foxg1 mutations in humans. ### Competing Interest Statement The authors have declared no competing interest.