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

Abstract

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, through TRAP-seq, we discovered that Foxg1 is implicated in the translation of hundreds of neuronal genes 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.