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, 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.

Foxg1 bimodally tunes L1-mRNA and -DNA dynamics in the developing murine neocortex

“…Hence, we propose that Foxg1 may ease L1- mRNA retro-transcription largely by preventing the interaction among the two helicases and L1- mRNA ( Goodier et al, 2012 ), either competitively or due to steric hindrance. Such involvement in retrotranscription control supports a role for Foxg1 in other non-transcriptional metabolic routines, such as post-transcriptional ncRNA processing ( Weise et al, 2019 ), translation ( Artimagnella et al, 2022 preprint) and mitochondrial biology ( Pancrazi et al, 2015 ).…”

“…They lead to severe neuropathological scenarios, collectively referred to as FOXG1 syndrome, for which no cure is so far available ( Brimble et al, 2023 ; ]; Florian et al, 2011 ; Mitter et al, 2018 ; Papandreou et al, 2016 ; ; Vegas et al, 2018 ). Traditionally recognized as a transcriptional transrepressor ( Seoane et al, 2004 ), Foxg1 has more recently been implicated in the straight control of extra-transcriptional functions, such as post-transcriptional ncRNA processing ( Weise et al, 2019 ), translation ( Artimagnella et al, 2022 preprint) and mitochondrial biology ( Pancrazi et al, 2015 ).…”

Foxg1bimodally tunesL1-mRNA and -DNA dynamics in the developing murine neocortex

“…Hence, we propose that Foxg1 may ease L1-mRNA retro-transcription largely by preventing the interaction among the two helicases and such mRNA [63], competitively or because of steric hindrance. Such involvement in retrotranscription-control adds to Foxg1 implication in a number of other non-transcriptional metabolic routines, such as post-transcriptional ncRNA processing [25], translation [26] and mitochondrial biology [27].…”

“…Heterozygosity for them results in a complex array of severe neuropathological scenarios, collectively referred to as FOXG1 syndrome, for which no cure is so far available [17][18][19][20][21][22][23]. Classically known as a transcriptional transrepressor [24], Foxg1 has been more recently implicated in straight control of extra-transcriptional functions, such as post-transcriptional ncRNA processing [25], translation [26] and mitochondrial biology [27]. Albeit tightly controlled [28,29], transposable elements including L1s are actively transcribed.…”