FOXG1 sequentially orchestrates subtype specification of postmitotic cortical projection neurons

Abstract

The mammalian neocortex is a highly organized six-layered structure with four major cortical neuron subtypes: corticothalamic projection neurons (CThPNs), subcerebral projection neurons (SCPNs), deep callosal projection neurons (CPNs), and superficial CPNs. Here, careful examination of multiple conditional knockout model mouse lines showed that the transcription factor FOXG1 functions as a master regulator of postmitotic cortical neuron specification and found that mice lacking functional FOXG1 exhibited projection deficits. Before embryonic day 14.5 (E14.5), FOXG1 enforces deep CPN identity in postmitotic neurons by activating Satb2 but repressing Bcl11b and Tbr1 . After E14.5, FOXG1 exerts specification functions in distinct layers via differential regulation of Bcl11b and Tbr1 , including specification of superficial versus deep CPNs and enforcement of CThPN identity. FOXG1 controls CThPN versus SCPN fate by fine-tuning Fezf2 levels through diverse interactions with multiple SOX family proteins. Thus, our study supports a developmental model to explain the postmitotic specification of four cortical projection neuron subtypes and sheds light on neuropathogenesis.

FOXG1 drives transcriptomic networks to specify principal neuron subtypes during the development of the medial pallium

“…Here, we showed a loss of RSC-PyNs (UL) and marked down-regulation of SATB2 in Foxg1 cKO mice. When viewed alongside our earlier findings that FOXG1 specifies neocortical callosal projection neurons through direct activation of Satb2 ( 10 ), our data support the notion that FOXG1 may also specify RSC-PyNs (UL) by acting as a transcriptional activator of Satb2 .…”

“…To explore whether FOXG1 directly represses Tbr1 during the specification of CA1-PyNs, we first performed ChIP-qPCR and detected a strong FOXG1 occupancy at a putative binding site 700 bp upstream of the Tbr1 transcription start site, as previously reported ( 10 ) ( Fig. 6B ).…”

“…Pou3f1 was reported to regulate transcription in differentiated neocortical neurons ( 41 ). Bcl11b and Fezf2 are known to be the key determinants for cortical subcerebral projection neurons ( 10 ).…”

“…RNA isolation, reverse transcription, and qPCR analysis RNA isolation, reverse transcription, and qPCR were performed as previously described (10). Neuro2a cells were harvested 72 hours after Zbtb20-shRNA or Tbr1-shRNA transfection.…”

“…The Forkhead-box TF FOXG1 has been demonstrated to control a variety of developmental processes ranging from dorsal-ventral pattern formation of the telencephalon and cell fate determination to cortical circuit specialization by exerting both repressive and activating functions ( 9 , 10 ). However, no study has examined the contribution of FOXG1 to postmitotic cell type specificity in the MP or the downstream targets of FOXG1 at single-cell resolution.…”