Screening the expression characteristics of several miRNAs in G93A‐SOD1 transgenic mouse: altered expression of miRNA‐124 is associated with astrocyte differentiation by targeting Sox2 and Sox9

Abstract

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 in situ 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 in vivo 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. Cover Image for this issue: doi: 10.1111/jnc.14171.

miR‐124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9

“…Moreover, overexpression of miR‐124 induces neuron‐specific differentiation by increasing β ‐III tubulin expression and decreasing GFAP expression (Jiao, Liu, Yao, & Teng, ). In contrast to our study, Zhou et al have shown that miR‐124 may regulate astrocyte differentiation by targeting Sox2 and Sox9 in amyotrophic lateral sclerosis transgenic mice (Zhou et al, ). Other miRNAs, such as miR‐145 , miR‐495 , and miR‐101 , are consistently downregulate the expression of Sox9 3′‐UTR reporter genes (Lee et al, ; Yang et al, ; Zhang et al, ).…”

Cortical Neurotoxic Astrocytes with Early ALS Pathology and miR-146a Deficit Replicate Gliosis Markers of Symptomatic SOD1G93A Mouse Model

“…Among other miRNAs suspected to contribute to ALS pathology is the altered expression of miR-146a and miR-21in the SC and brainstem of ALS transgenic mice [81]. Similarly to these authors we also found reduced miR-146a levels in the cortical homogenates, a feature not observed in the SC from the same mSOD1 mice model, in either stage 1 or stage 2 [19].…”

MiR-124 and the Underlying Therapeutic Promise of Neurodegenerative Disorders

“…In addition, the elevated levels seem to be negatively correlated with the STAT3 transcription factor, a key factor for neural differentiation and cell survival (Marcuzzo et al, 2014). In a study of neural stem cells from ALS transgenic mice, Zhou et al (2018) showed that miR-124 was downregulated in the brainstem and spinal cord, and that miR-124 may participate in astrocyte differentiation of ALS transgenic mice by targeting Sox2 and Sox9. Many studies have reported that the expression level of miR-124 is inconsistent in ALS models, which may be related to the samples selected by different studies, and more studies in the future may draw more clear conclusions.…”