Deletion of Astroglial Dicer Causes Non-Cell-Autonomous Neuronal Dysfunction and Degeneration

Abstract

The endoribonuclease, Dicer, is indispensible for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in mammalian central nervous system. While functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here we report the effect of Cre-loxP mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology prior to postnatal week 5. Thereafter mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements and premature death by postnatal week 9–10. Integrated transcription profiling, histological and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state prior to the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders.

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.…”

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

“…Otherwise, this would not be the first time that changes to genes in astrocytes at an epigenetic level are seen to influence normal neuronal function. For instance, Tao and colleagues showed that selectively knocking-out Dicer in astrocytes leads to neuronal dysfunction and degeneration 62 . Thus far BEGAIN has been investigated and localized in nuclei and synapses of neurons 56 , but there is no information on its relation to astrocytes.…”

MicroRNAs as biomarkers in molecular diagnosis of refractory epilepsy

“…Dicer is an RNase III essential to the cleavage of pre-miRNA to mature miRNA. The deletion of Dicer in the neural system typically leads to neuronal dysfunction, neurodegeneration, macular degeneration, epilepsy seizure and cognitive deficits [53][54][55][56][57]. The loss of Dicer appears specific to TLE patients with HS and cause a failure of miRNA biogenesis, which further gives rise to degenerative changes in cortex and hippocampal morphology that have been observed in human epilepsy [54].…”