摘要
N^(6)-methyladenosine(m^(6)A)modification,which is achieved by the METTL3/METTL14/WTAP methyltransferase complex,is the most abundant internal mRNA modification.Although recent evidence indicates that m^(6)A can regulate neurodevelopment as well as synaptic function,the roles of m^(6)A modification in the cerebellum and related synaptic connections are not well established.Here,we report that Purkinje cell(PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death.Loss of Wtap also causes the aberrant degradation of multiple PC synapses.WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m^(6)A methylation in PCs.Moreover,the expression of GFAP and NF-L in the degenerating cerebellum is increased,suggesting severe neuronal injuries.In conclusion,this study demonstrates the critical role of WTAP-mediated m^(6)A modification in cerebellar PCs,thus providing unique insights related to neurodegenerative disorders.
基金
supported by the National Natural Science Foundation of China(82121003,81970841,and 81790643)
the Department of Science and Technology of Sichuan Province(2021YFS0386,2021YFS0369,20ZYD038,20ZYD037,2020JDZH0026,2021JDZH0022)
the CAMS Innovation Fund for Medical Sciences(2019-12M-5-032)
Huanhua Distingished Scholar grant
the Department of Chengdu Science and Technology(2021-YF05-01316-SN)。
