Understanding the Role of Dicer in Astrocyte Development

Abstract

The Dicer1 allele is used to show that microRNAs (miRNAs) play important roles in astrocyte development and functions. While it is known that astrocytes that lack miRNAs are dysregulated, the in vivo phenotypes of these astrocytes are not well understood. In this study, we use Aldh1l1-EGFP transgene, a marker of astrocytes, to characterize mouse models with conditional Dicer1 ablation (via either human or mouse GFAP-Cre). This transgene revealed novel features of the defective astrocytes from the absence of miRNA. Although astrocyte miRNAs were depleted in both lines, we found histological and molecular differences in the Aldh1l1-EGFP cells between the two Cre lines. Aldh1l1-EGFP cells from hGFAP-Cre mutant lines displayed up-regulation of Aldh1l1-EGFP with increased proliferation and a genomic profile that acquired many features of wildtype primary astrocyte cultures. In the young mGFAP-Cre mutant lines we found that Aldh1l1-EGFP cells were disorganized and hyperproliferative in the developing cerebellum. Using the Aldh1l1-EGFP transgene, our work provides new insights into the roles of miRNAs in astrocyte development and the features of astrocytes in these two mouse models.

Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection

“…shown in numerous studies to have reliably astrocyte-specific expression (22)(23)(24)(25). Consistent with this, we observed deletion of Ifnar on cortical and cerebellar astrocytes, with intact expression of the receptor on nonastrocytic cells.…”

“…Given the findings from our own studies demonstrating that IFNAR signaling in astrocytes enhances in vitro BBB integrity in response to WNV (4), we used Ifnar fl/fl Gfap-Cre mice, in which IFNAR signaling was abrogated in glial fibrillary acidic protein-expressing (GFAP-expressing) astrocytes, to evaluate the contribution of astrocyte IFNAR signaling to WNV pathogenesis and disease. For these studies, we chose the Gfap-Cre line 77.6, which was previously shown to exhibit a Cre expression that is more specific to astrocytes than to other GfapCre lines (22)(23)(24)(25). We also used an established in vitro BBB model to examine how forebrain versus hindbrain astrocytes differentially regulate barrier function.…”

The microRNA expression profile of mouse Müller glia in vivo and in vitro

“…Next to miR-204, the next most highly expressed MG miRNAs (with less than 20% expression in neurons) were miR-125b, and miR-9. These two miRNAs are also highly expressed in P7 FAC-sorted astrocytes of the forebrain, along with several others of the most highly expressed mGliomiRs (miR-99a, miR-204, miR-135a) and shared miRs (miR-720, let-7b, miR-29a, and miR-30d) 40 . A role for miR-125b and miR-9 has been described for retinal development, particularly in the transition from early (non-gliogenic) to late (gliogenic) progenitors 41 , as well as its role during neurogenesis 42 43 .…”

Astrocyte-Derived Small Extracellular Vesicles Regulate Dendritic Complexity through miR-26a-5p Activity

“…In order to identify molecular cargoes in astrocyte-derived sEVs able to promote morphological changes in neurons, we took advantage of a comprehensive study by Jovičić et al identifying miRNAs in total homogenates from cultured astrocytes [33]. To generate a robust short-list of candidates, we selected the most abundant miRNAs (cycle threshold < 25), which have been confirmed to be present in astrocytes by at least one other independent study [13,[34][35][36][37][38][39][40][41][42]. Then, the identified candidates, namely miR-26a5p, miR-23a-5p, miR-223a-5p, miR-19a-5p, miR-32a-5p, miR-146a-5p, miR-181-5p, and miR-29a-5p, were categorized using a selection algorithm according to the function of their predicted targets (see Methods; Figure 3A).…”