Study On The Mechanism Of Foxg1 Regulating The Subtype Specification Of Corticofugal Neurons

The neocortex of mammal has a typical six layer structure.According to different axonal projection,the deep corticofugal neurons(CFuNs)are divided into corticothalamic projection neurons(CThPNs)of L6 and subcerebral projection neurons(SCPNs)of L5 in early neurogenesis.These different subtypes of neurons form an information output system between cerebral cortex and cortex-subcortical parts precisely regulating voluntary movement and participating in information feedback.The specification of exocortex neurons requires multiple layer-specific molecules.Transcription factor Foxg1 plays various roles in telencephalon development,including cell proliferation,differentiation,migration,localization and subtype specification.The patients with FOXG1 syndrome that are caused by Foxg1 mutation show typical sensorimotor dysfunction,such as apraxia dystonia early onset hyperkinesia rigid movement,suggesting that dysplasia and dysfunction are relate to hypocortical neurons,but the specific mechanism is not clear.We construct two mice with Foxg1 specific knockout at different time nodes including NEX-Cre;Foxg1 c KO and the CAG-Cre ER;Foxg1 c KO to investigate the effect of Foxg1 deletion on the development of corticofugal neurons,our results confirm that the Foxg1 regulates the subtype specification of corticofugal neurons in both time-specific and subtype-specific ways.First of all,Foxg1 accurately regulates the high expression of Fezf2 in early CFuNs and specific expression patterns of SCPNs and CThPNs subtypes in later stage by activating the transcriptional expression of Sox5,Sox4,Sox11 and synergistically interacting with Sox molecules to guarantee the ordered specification of CFuNs to CThPNs and SCPNs.Secondly,Foxg1 also promoted the specification of SCPNs by directly inhibiting Tbr1 transcription and down-regulating the expression of Tbr1 in SCPNs.Thirdly,Foxg1 promotes the specification of CThPNs by directly inhibiting the transcription of Bcl11 b and down-regulating the expression of Bcl11 b in CThPNs.Our research shows that Foxg1 recruits and organizes a complex transcriptional regulatory network to precisely control the ordered specification of cortical neurons.This study deepens realization of the molecular mechanisms that regulate the specification of corticofugal neurons and provides important clues for the FOXG1 syndrome.