Foxg1 is an ancient transcription factor gene orchestrating a number of neurodevelopmental processes taking place in the rostral brain. In this study, we investigated its impact on neocortical activity. We found that mice overexpressing Foxg1 in neocortical pyramidal cells displayed an electroencephalography (EEG) with increased spike frequency and were more prone to kainic acid (KA)-induced seizures. Consistently, primary cultures of neocortical neurons gain-of-function for Foxg1 were hyperactive and hypersynchronized. That reflected an unbalanced expression of key genes encoding for ion channels, gamma aminobutyric acid and glutamate receptors, and was likely exacerbated by a pronounced interneuron depletion. We also detected a transient Foxg1 upregulation ignited in turn by neuronal activity and mediated by immediate early genes. Based on this, we propose that even small changes of Foxg1 levels may result in a profound impact on pyramidal cell activity, an issue relevant to neuronal physiology and neurological aberrancies associated to FOXG1 copy number variations.

Highlights d PIN1 stabilizes HP1a in complex with LaminB in a phosphorylation-dependent manner d PIN1 function maintains nuclear envelope structure under mechanical stress d PIN1 loss causes HP1a degradation, heterochromatin relaxation, transposon derepression d Loss of PIN1 nucleo-protective function contributes to Alzheimer's disease

Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, Foxg1 has been also detected outside the nucleus, however biological meaning of that has been only partially clarified. Here, moving from Foxg1 expression in cytoplasm of neocortical neurons, we investigated its implication in translational control. We documented an impact of Foxg1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that Foxg1 increases Grin1 protein level by enhancing translation of its mRNA, while not increasing its stability. Such enhancement was associated to augmented translational initiation and, possibly, polypeptide elongation. Molecular mechanisms at the basis of this activity included Foxg1 interaction with Eif4e and Eef1d as well as with Grin1-mRNA. Besides, we found that, within murine neocortical cultures, Grin1 de novo synthesis undergoes a prominent and reversible, homeostatic regulation and Foxg1 is instrumental to that. Finally, trough TRAP-seq, we discovered that Foxg1 is implicated in the translation of hundreds of neuronal at the level of ribosome engagement and progression. All that points to Foxg1 as a key effector, crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.