Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina.
MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs, and removal of Dicer has been shown to disrupt many developmental processes. In this study, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knock-out mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at postnatal day 16, which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic electroretinogram (ERG) responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer-depleted retinas showed a decrease in several miRNAs. The observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.
Damiani
Devid
D
Neuroscience Institute, Italian National Research Council, 56100 Pisa, Italy.
Alexander
John J
JJ
O'Rourke
Jason R
JR
McManus
Mike
M
Jadhav
Ashutosh P
AP
Cepko
Constance L
CL
Hauswirth
William W
WW
Harfe
Brian D
BD
Strettoi
Enrica
E
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D018450:Disease Progression; D004596:Electroretinography; D004722:Endoribonucleases / Q000235:genetics*; D020868:Gene Silencing; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009030:Mosaicism; D010641:Phenotype; D012160:Retina / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D043244:Ribonuclease III / Q000235:genetics*
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases