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Transcript
Title: MicroRNA ablation affects Bergmann glial morphology and disrupts tissue morphogenesis in the developing mouse cerebellum Yi Kuang1, 4, 6, Qian Liu1, 6, Ning Huang1, 4, Jun Li1, Xiaoqiong Shu1, Chi Zhang1, 4, Mei Jiang1, Q. Richard Lu5 and Hedong Li1, 2, 3, * 1 West China Developmental & Stem Cell Institute, 2Department of Pediatrics, 3Key Laboratory of Obstetric&Gynecologic and Pediatric Diseases and Birth Defects, Ministry of Education, West China Second University Hospital, 4School of Life Science, Sichuan University, Chengdu 610041, P.R. China 5 Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 6 These authors contributed equally to this work *Correspondence should be addressed to: Dr. Hedong Li Tel. 86-28-85501982 E-mail: [email protected] Keywords: hGFAP, miR-9, Dicer, Cre-flox, Bergmann glia. Abstract: MicroRNAs (miRNAs) play important roles during development of the central nervous system (CNS). Several reports indicate that tissue development and cellular differentiation in the developing forebrains are disrupted in the absence of miRNAs. However, miRNA functions during cerebellar development have not been systematically characterized. Here we conditionally knockout Dicer gene under the activity of human glial fibrillary acidic protein (hGFAP) promoter to examine the effect of miRNAs in the developing cerebellum. We found that ablation of miRNAs resulted in a smaller cerebellum, mis-positioned Purkinje neurons, decreased proliferation and increased apoptosis in granule neuron precursors, decreased number of basket and stellate interneurons and aberrant morphology of Bergmann glia. In addition, Notch1 signaling appears to be blocked in miRNA-ablated Bergmann glia. We further identified miR-9 as differentially expressed in Bergmann glial cells, and its expression was promoted by Notch1 activation. We also demonstrated that cortical radial glia exhibited normal morphology in the absence of miRNAs and yet reduced radial glial marker expression at embryonic stage, and that the postnatal radial glial transition to astrocytes was promoted in miRNA-ablated forebrains. These results further stressed the critical involvement of miRNAs in the developing CNS including cerebellum and provided first evidence of differential miRNA function in regulating radial glial phenotype in different regions of the developing CNS.