The Mechanism Of MicroRNAs In Central Nervous System

microRNAs are a class of small non-coding single stand RNAs,consisting of 19-23 nucleotides in length.They are evolutional conserved and regulate gene expression at post-transcriptional level which lead to further biological functions.With the introduction of secreted microRNA,microRNAs are regarded as not only intracellular regulatory molecules but also a new form of intercellular communication.These exogenous microRNAs can function as endogenous microRNAs to regulate the target gene expression and the function of recipient cells.microRNAs are abundant in the nervous system,where they have key roles in development and are likely to be important mediators of plasticity.They also have emerging roles in neurological disease.In this thesis,we focus on the microRNA functions in the nervous system from the following two aspects:secreted microRNA and intracellular microRNA.We first investigated the role of secreted microRNA in neuron modulation:secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neuron to neurotoxin by targeting Bcl-2.Our results demonstrated that after LPS stimulation,astrocyte released shedding vesicles(SVs),which enhanced the vulnerability of DA neurons to neurotoxin.Further investigation showed that increased astrocytic miR-34a in SVs was involved in this progress via targeting anti-apoptotic protein Bcl-2 in DA neurons.We also found that functionally block the astrocytic miR-34a in neuroinflammation can slow down the DA neurons loss under neurotoxin stress condition.These data revealed a novel mechanism underlying astrocyte-neuron interaction in disease condition.Besides,the increase of astrocytic miR-34a in neuroinflammation condition may be a potential target for alleviation the disease progress.We also investigated the role of intracellular microRNA in neuron homeostasis:role of miR-17 family in the negative feedback loop of BMP signaling in neuron.In the present study,we found that the expression of miR-17 family was elevated responding to BMP2 treatment.Then,we demonstrated that the activation of Smads by BMP2 directly increased the transcription of miR-17-92 and miR-106b-25 cluster,which include 4 members of miR-17 family,while the over-expression of miR-17 family repressed the protein level of BMPRII in primary neurons.In addition,our data also revealed an anti-apoptotic role of miR-17 family.Taken together,these results suggest a regulatory pathway of BMP-miR-17 family-BMPRII,which consist a negative feedback loop that balances BMP signaling and maintains cell homeostasis in neuron.In summary,this study provides the first demonstration that astrocytes communicate with neurons by transfer of microRNAs via SVs.During this procession,the secreted microRNAs may serve as mediators of a new form of intercellular communication in nervous system.Meanwhile,microRNAs can also serve as nodes of signaling networks that ensure cell homeostasis in neuron.These conclusions will be important in understanding the role of microRNAs in the nervous system and the way they function.