Expression Of Acot7 In Oligodendrocytes And Its Function In Myelin Development

Objective: Myelin is a multilayer and spiral structure,wrapping around the axons.It is essential for the protection of axons,insulation and maintenance of the saltatory conduction of the action potential.Since myelin membrane is rich in lipids,the integrity of myelin is susceptible to numerous lipid metabolism disorders.Fatty acid is one of the most important components of the myelin structure.Several neurological diseases caused by fatty acid metabolism are associated with defects in myelin that are mostly due to the accumulation of lipids,such as Sjogren-Larsson syndrome,Refsum disease,adrenoleukodystrophy.Therefore,study on fatty acid metabolism is essential.Acyl-coenzyme A thioesterases(Acots)are enzymes that catalyze the hydrolysis of acyl-CoAs to free fatty acid(FFA)and free CoA.Acot7,a member of the Acots,is rich and bears almost all acyl-CoA thioesterase activity in the brain.It was shown that the expression of Acot7 in neurons and could protect neurons against neurotoxicity.However,no research about Acot7 on other nerve cells has been reported.Oligodendrocytes(OLs),differentiated from Oligodendrocyte Progenitor Cells(OPCs),are producing the myelin sheath in the central nervous system(CNS).They are crucial for myelination and maintainence of myelin sheath.So is Acot7 expressed in OLs? If it is expressed,does it play a role in myelination? We focused on the expression and function of Acot7 in OLs,and further explored its effect on myelin formation.We hope to gain a deeper understanding on the function and underlying mechanism of Acot7 in myelin fatty acid metabolism.Methods: In this study,immunofluorescence staining,Western Blot analysis and flow cytometry were used to determine the expression of Acot7 in OLs,including expression patterns under normal development and pathological conditions.Acot7 function was studied by purified OPCs infected with Acot7 overexpressing and interfering lentivirus in vitro.Further,conditional knockout mice were used to examine the effects of Acot7 on myelin structure and motor function.Results: Here we found that Acot7 was highly expressed in OLs and had scarce expression in microglia and astrocytes.We also observed that the expression pattern of Acot7 in white matter during developmental process or damage repair was closely associated with myelination or remyelination.Down-regulation Acot7 in cultured OPCs inhibited their differentiation,and up-regulation of Acot7 promoted their differentiation,without affecting the proliferation,apoptosis or migration of OPCs.Conditional knockout(cKO)of OL-Acot7 resulted in thinner myelin sheath and hypomyelination.And the proportion of mature OLs in the white matter of the spinal cords of Acot7 cKO mice was lower than that of the control littermates during development.However,these changes recovered in adults.Interestingly,about 50% of OLs in white matter of the central nervous system expressed Acot7,suggesting that Acot7 may be involved in the heterogeneity of OLs.Conclusions: Acot7 is selectively expressed in OLs and is up-regulated in OLs during myelination and remyelination.Acot7 promotes the differentiation of cultured OPCs,while conditional knockout of OL-Acot7 causes hypomyelination at the developmental stage.Together,our data indicate that Acot7 plays a crucial role in myelin development.