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The Cerebellum

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01.04.2017 | Original Paper

Dicer1 Ablation Impairs Responsiveness of Cerebellar Granule Neuron Precursors to Sonic Hedgehog and Disrupts Expression of Distinct Cell Cycle Regulator Genes

verfasst von: Qian Liu, Mei Jiang, Yi Kuang, Xiaoqiong Shu, Jun Li, Matthew W. Li, Hedong Li

Erschienen in: The Cerebellum | Ausgabe 2/2017

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Abstract

Granule neuron precursors (GNPs) proliferate under the influence of Sonic hedgehog (Shh) that is secreted by Purkinje neurons during early postnatal cerebellar development. To investigate microRNA (miRNA) function in this developmental process, we conditionally deleted the Dicer1 gene under the activity of human glial fibrillary acidic protein (hGFAP) promoter. We report that Dicer1-ablated GNPs display decreased proliferation and survival at early postnatal stages and that the proliferation defect of mutant GNPs cannot be rescued by treatment of an Shh agonist in vitro as assayed by 5-bromo-2′-deoxyuridine (BrdU) pulse labeling and Shh target gene expression detection. Further analysis reveals that the expression of distinct cell cycle regulator genes including cell cycle inhibitor, CDKN1a (p21), selectively increases in Dicer1-ablated GNPs. Subsequently, we demonstrate that miR-17-5p exhibits high expression level in the developing cerebellum and that transfection of a synthetic miR-17-5p mimic downregulates p21 protein expression in GNPs and promotes proliferation of GNPs in culture. Therefore, Dicer1 ablation impairs Shh-induced GNP proliferation by disrupting the expression of distinct cell cycle regulator genes that are targets of miR-17∼92 cluster members. This study establishes a molecular link between miRNAs and cell cycle progression in the proliferating GNPs during normal cerebellar development and may facilitate miRNA application in treating medulloblastoma.

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Titel: Dicer1 Ablation Impairs Responsiveness of Cerebellar Granule Neuron Precursors to Sonic Hedgehog and Disrupts Expression of Distinct Cell Cycle Regulator Genes
verfasst von: Qian Liu
Mei Jiang
Yi Kuang
Xiaoqiong Shu
Jun Li
Matthew W. Li
Hedong Li
Publikationsdatum: 01.04.2017
Verlag: Springer US
Erschienen in: The Cerebellum / Ausgabe 2/2017
Print ISSN: 1473-4222
Elektronische ISSN: 1473-4230
DOI: https://doi.org/10.1007/s12311-016-0821-x

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