期刊
JOURNAL OF NEUROCHEMISTRY
卷 145, 期 1, 页码 51-67出版社
WILEY
DOI: 10.1111/jnc.14229
关键词
amyotrophic lateral sclerosis; astrocyte; miRNAs; neural stem cells; Sox2; Sox9
资金
- National Natural Science Foundation of China [81271413, 81401066]
- Shandong Province Science and Technology Development Program of China [2012GSF11827]
- Shandong Province Natural Science Foundation of China [ZR2012HQ021, ZR2016HM60, ZR2016HL20]
- Shandong Province Education Department of China [J12LK51, J11LF16, J13LK05]
- Muscular Dystrophy Association [254530]
- Brigham and Women's Hospital BRI Fund to Sustain Research Excellence
- Bill & Melinda Gates Foundation [01075000191]
- Shandong Province Taishan Scholar Project
- Key Lab of Neurological Disease and Regeneration & Repair of Weifang Medical University
MicroRNAs (miRNAs) are suspected to be a contributing factor in amyotrophic lateral sclerosis (ALS). Here, we assess the altered expression of miRNAs and the effects of miR-124 in astrocytic differentiation in neural stem cells of ALS transgenic mice. Differentially expressed miRNA-positive cells (including miR-124, miR-181a, miR-22, miR-26b, miR-34a, miR-146a, miR-219, miR-21, miR-200a, and miR-320) were detected by insitu hybridization and qRT-PCR in the spinal cord and the brainstem. Our results demonstrated that miR-124 was down-regulated in the spinal cord and brainstem. In vitro, miR-124 was down-regulated in neural stem cells and up-regulated in differentiated neural stem cells in G93A-superoxide dismutase 1 (SOD1) mice compared with WT mice by qRT-PCR. Meanwhile, Sox2 and Sox9 protein levels showed converse change with miR-124 invivo and vitro. After over-expression or knockdown of miR-124 in motor neuron-like hybrid (NSC34) cells of mouse, Sox2 and Sox9 proteins were noticeably down-regulated or up-regulated, whereas Sox2 and Sox9 mRNAs remained virtually unchanged. Moreover, immunofluorescence results indicated that the number of double-positive cells of Sox2/glial fibrillary acidic protein (GFAP) and Sox9/glial fibrillary acidic protein (GFAP) was higher in G93A-SOD1 mice compared with WT mice. We also found that many Sox2- and Sox9-positive cells were nestin positive in G93A-SOD1 mice, but not in WT mice. Furthermore, differentiated neural stem cells from G93A-SOD1 mice generated a greater proportion of astrocytes and lower proportion of neurons than those from WT mice. MiR-124 may play an important role in astrocytic differentiation by targeting Sox2 and Sox9 in ALS transgenic mice.
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