Essential Role Of PDK1/Akt Signaling In Oligodendrocyte Development

Oligodendrocytes(OLs)are the myelinating cells in the central nervous system(CNS)which produce the insulating myelin sheath and promote rapid electrical conduction of nerve impulses.Besides,OLs also support axons through suppling energy and nutrition.When the function of oligodendrocyte is disrupted it will cause demyelination disease like multiple sclerosis.OL development is a complex and orchestrated progress.Once specified from multipotent neuroepithelial progenitor cells,OL precursor cells(OPCs)proliferate and migrate throughout the whole CNS.Some of them undergo a terminal differentiation event into myelinating OLs in their final position while some remain stem cells in the whole life.Akt(also known as PKB)is a key serine/threonine(S/T)kinase and belongs to the AGC family of protein kinases(Pearce et al.,2010).It is well known that Akt plays important roles in cell growth,cell survival,metabolism and human diseases.The activity of Akt is mainly regulated by 3-Phosphoinositide dependent protein kinase-1(PDK1)which phosphorylates Akt on the residue of threonine 308(T308).However,it has been elusive how PDK1/Akt signaling regulates oligogenesis in the central nervous system.This study focuses on the function and mechanism of PDK1/Akt signaling in OL development.In order to research the function and mechanism of PDK1/Akt signaling in the OL development,we mainly used mice model by genetictechnology.Firstly,we generated oligodendrocyte lineage cells specificPDK1 conditional knockout(PDK1 cKO)mice.We found that deletion of PDK1 caused deficient OL differentiation during OL development,suggesting PDK1 is required for OL differentiation.Secondly,considering that the activity of Akt is dependent on PDK1,we studied the function of Akt in the OL development.Because there exist three Akt isoforms,we first examined whether single isoform affected OL development.We showed that Akt1,Akt2 or Akt3 knockout(KO)mice did not exhibit significant changes on oligodendrocytes and OL precursor cells,suggesting that deletion of Akt single isoform doesn't have effect on OL development.Thirdly,considering the functional redundancy between Akts,we generated OL lineage cells specificAkt1,Akt2 and Akt3 triple conditional KO(termed as Akt cTKO)mice.We found complete loss of mature OLs and myelination,reduced OPCs and no increased apoptoticcells in Akt cTKO mice,indicating that Akt is required for OL differentiation and myelination although it can also promote the proliferation of OPCs in the CNS.Finally,we explored the mechanism of PDK1/Akt signaling regulating OL differentiation.We found that phosphorylation of FoxO1 by Akt triggered their cytoplasmictranslocation which led to inactivity of FoxO1.Additionally,activated FoxO1 inhibited Sox10 expression even under the promotion of Olig2 through binding with the promoter of Sox10.Thus,phosphorylation of FoxO1 by Akt triggered their cytoplasmictranslocation,which subsequently permitted Olig2 to activate the expression of Sox10 and downstream genes.Taken together,these results highlight an essential role of the PDK1/Akt signaling in governing OL differentiation during postnatal development.In addition,this study has identified a novel mechanism for OL differentiation,in which Akt couples with FoxO1 to regulate Olig2-dependent activation of Sox10.Our study is not only helpful for us to understand the physiology of oligodendrocyte development,but also the pathology of various OL-related diseases.