The Function Of FOXG1 During The Development Of The Hippocampus

Foxg1(Forkhead box G1),a member of the Forkhead transcription factor family,is widely expressed in the telencephalon and plays important roles in regulating neural development at different stages and specialization in subtypes of neurons.Mutations(duplication,deletion,point mutation or frame shift mutation)in FOXG1 leads to FOXG1 syndrome,in which patients exhibit epilepsy,severe mental retardation,language impairement,suggesting an important role in hippocampal development.The WNT signaling pathway plays key roles in various developmental processes,but its role in hippocampal development and regulatory mechanism needs to be deeply studied.WNT5A,which activates the noncanonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Previous studies have shown that there are complex interactions between Foxg1 and WNT signaling pathways in different developmental events.Foxg1 is strongly expressed in the early stages of hippocampal development until adulthood,and plays an important role in hippocampal development.Here,through conditional disruption of Foxg1 in the hippocampal progenitors since E10.5 and the postmitotic neurons achieved by crossing Foxg1^fl/fl with Emx1-Cre and Nex-Cre respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was obviously upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.Foxg1 regulates Wnt5a different extent in neurons at different developmental stages and affects hippocampal development at different levels.We further demonstrated that FOXG1 directly represses Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and WNT signaling,helping to elucidate the mechanisms underlying hippocampal development and provide certain foundational data for understanding the pathogenesis of FOXG1 syndrome.