The Role Of Foxg1 In Regulating Mitochondrial Dynamics And Neural Plasticity

The transcription factor Foxg1 is demonstrated to play a key role in telencephalic development.Mutations in FOXG1 lead to FOXG1 syndrome that exhibits social and cognitive disabilities.Previous studies on Foxg1 were mainly focused on the telencephalic development.However,the high expression level of Foxg1 in postmitotic and mature neurons strongly indicates that Foxg1 may also play important roles in postnatal stages and in adulthood.Mitochondria are the main energy supplier in the eukaryotic cell and regulate a variety of cellular activities.The morphologies of mitochondria vary from distinct cell types and physiological states,which is vital to cell metabolic activity.However,the mechanism underlying the fusion/fission dynamics is still unclear.Hereby conditional deleting of Foxg1 in post-mitotic and mature neurons,we reported that Foxg1 was involved in the regulation of mitochondrial dynamics and neural plasticity.Knockout of Foxg1 brought about elongated and aggregated mitochondria as well as mitochondrial membrane potential loss.Knockdown of Foxg1 in neural cell line showed identical results indicated that Foxg1 was required for the mitochondrial dynamic.We further demonstrated that Foxg1 regulated mitochondrial dynamics by directly activates fusion element Opa1.Overexpression of Opa1 partially restored the mitochondrial structure abnormalities caused by Foxg1 deletion in vitro.Additionally,we found that a spliceosome of FOXG1 was localized in the mitochondria and may also contribute to the regulation of mitochondrial dynamics.Interestingly,post-mitotically deletion of Foxg1 led to the reduction of dendrite and axon growth.While ablation of Foxg1 in mature neurons resulted in dendrite and spine loss,synaptic structure abnormalities and reduced synaptic transmission.Furthermore,the Foxg1 deletion mice exhibited a remarkable reduction in Schaffer-collateral long-term potentiation and impaired social and learning and memory-related behaviors.Together,we demonstrate that Foxg1 is important for the regulation of mitochondrial dynamics,which may,in turn,contribute to the neural plasticity.Our results put new insight into understanding the molecular mechanism of FOXG1 syndrome.