Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1.

Background: 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.

Results: Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the 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 the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference.

Conclusions: These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.