The Role Of PDK1 In The Development Of Cortical Inhibitory Interneurons And Excitatory Neurons

The higher function of cerebral cortex mainly depends on the functional neural circuits that composed of excitatory neurons and inhibitory interneurons.The maintenance of the excitatory/inhibitory balance is the basis of the function of neural circuits.During the development cortical interneurons originate from the ganglionic eminence and migrate to the dorsal cortex by tangential migration.Excitatory neurons are produced form the ventricular zone（VZ）of the dorsal telencephlon.However,the mechanisms underlying the development of cortical interneurons and excitatory neurons remain unclear.3-Phosphoinositide-dependent protein kinase-1（PDK1）is a highly conserved threonine/serine kinase in the AGC kinase family,and has been reported to acts as an important member of the PI3 K signaling pathway,regulating multiple downstream effectors to affect a series of biological processes such as cell proliferation and growth,neural differentiation,cell migration and survival.Tthis study aims to explore the roles of PDK1 in the development of inhibitory and excitotary neurons.First,we reported that the conditional knockout of Pdk1 in progenitors of the subpallium ganglionic eminences achieved by crossing the Dlx5/6-Cre-IRES-EGFP line with Pdk1^fl/fl mice led to the severely increased apoptosis of immature interneurons,subsequently resulting in a significant decrease in cortical interneurons.However,the tangential migration,progenitor pools and cell proliferation were not affected by the disruption of Pdk1.We further found the activity of AKT-GSK3β signaling pathway was decreased after Pdk1 deletion,suggesting it might be involved in the regulation of the survival of interneurons.We also explored the function of PDK1 in the development of cortical excitatory neurons.During cortical development,the early generated deeper-layer neurons are mainly generated by apical progenitors（APs）in the ventricular zone（VZ）of the cortex,while the relatively late generated upper-layer neurons are mainly generated by basal progenitors（BPs）in the subventricular zone（SVZ）of the cortex.In the early stages of neurodevelopment,APs can self-renew by symmetric division.With the continuous progress of neurogenesis,APs gradually transitions from symmetric division to asymmetric division,mainly producing an AP and a deeper-layer neuron or BP by asymmetric division,and the length of G1 phase is also continuously extended.However,the regulatory mechanism of APs transition to BPs and the length of G1 phase during neurogenesis is still unclear.Here,we reported that the conditional knockout of Pdk1 in progenitors of the dosal cortex achieved by crossing the Emx1-Cre line with Pdk1^fl/fl mice led to a change in the direction of the cell division plate during neurogenesis,our further study found that PDK1 regulated the asymmetric division of APs by affecting the Notch signaling pathway and the a PKC-Par3/Par6 complex,and then regulated the transition process from APs to BPs,finally affecting the output of deeper-layer and upper-layer neurons.Meanwhile we also found that PDK1 regulated the G1 phase length of APs through inhibiting the activity of Myc-Cyclin D1 signaling pathway,thus effecting the balance between proliferation and differentiation of APs.In summary,PDK1 plays an important role in the development of inhibitory interneurons and excitatory neurons.