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| Status |
Public on May 10, 2011 |
| Title |
Deletion of astroglial Dicer causes cell non-autonomous neuronal dysfunction and degeneration |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Four replicate experiments using samples derived from biologically independent pairs of control (mGfap-Cre; Dicer +/flox) and Dicer mutant (mGfap-Cre; Dicer flox/flox) littermate mice (postnatal day 30) were performed with a dye-swap experimental design.
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| Contributor(s) |
Tao J, Wu H, Sun YE |
| Citation(s) |
21632951 |
| Submission date |
Apr 13, 2011 |
| Last update date |
May 10, 2018 |
| Contact name |
Yi Sun |
| E-mail(s) |
ysun@mednet.ucla.edu
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| Phone |
310-825-9506
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| Organization name |
UCLA
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| Department |
Molecular and Medical Pharmacology
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| Street address |
635, Charles E. Young Dr. South
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL4134 |
Agilent-014868 Whole Mouse Genome Microarray 4x44K G4122F (Feature Number version) |
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| Samples (4)
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| GSM707668 |
Control vs Dicer mutant cerebellum, Replicate 1 |
| GSM707669 |
Control vs Dicer mutant cerebellum, Replicate 2 |
| GSM707670 |
Control vs Dicer mutant cerebellum, Replicate 3 |
| GSM707671 |
Control vs Dicer mutant cerebellum, Replicate 4 |
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| Relations |
| BioProject |
PRJNA139117 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE28589_RAW.tar |
69.6 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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