Foxg1 control of neuronal morphology

The architecture of neocortical projection neurons is subject of a complex gene control. Here we demonstrated that Foxg1, a transcription factor gene which patterns the early rostral brain and sets the pace of telencephalic neuronogenesis, specifically stimulates dendrite elongation. This phenomenon occurs in vivo like in vitro, and it is detectable even upon moderate changes of Foxg1 expression levels. We found that Foxg1 acts by (a) stimulating Hes1, which in turn upregulates the well-known prodendritogenic effector pCreb1, and (b) downregulating Syt and Ndr1, namely two established antagonizers of dendrite elongation. Foxg1 impact on Hes1 turned out to stem from direct transactivation and indirect derepression. The latter was mediated by knock-down of Nfia and Sirt1, which normally antagonize Hes1 transcription. Next, Foxg1-driven pCreb1 upregulation required PKA and AKT, and correlated with reduced PP1 and PP2A phosphatase activity. Finally, Foxg1/Hes1 circuitry mastering dendritogenesis included two key homeostatic branches, i.e. Hes1-dependent Foxg1 downregulation and Syt upregulation. These findings contribute to clarify normal neurodevelopmental and activityrelated regulation of neuritogenesis. They further suggest that an abnormal sizing of the dendritic tree of neocortical projection neurons may occur in West and Rett syndrome patients with anomalous FOXG1 allele dosages and contribute to their neuropathological profiles.