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The Journal of Neuroscience, May 7, 2008, 28(19):4878-4887; doi:10.1523/JNEUROSCI.0828-08.2008

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Development/Plasticity/Repair
Dicer Inactivation Leads to Progressive Functional and Structural Degeneration of the Mouse Retina

Devid Damiani,¹ John J. Alexander,² Jason R. O'Rourke,³ Mike McManus,⁴ Ashutosh P. Jadhav,⁵ Constance L. Cepko,⁵ William W. Hauswirth,² Brian D. Harfe,³ and Enrica Strettoi¹

¹Neuroscience Institute, Italian National Research Council, 56100 Pisa, Italy, ²Departments of Ophthalmology and ³Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32608, ⁴Department of Microbiology and Immunology, University of California, San Francisco, California 94142, and ⁵Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to either of the following: Dr. Enrica Strettoi, Istituto di Neuroscienze CNR, Via G. Moruzzi 1, 56100 Pisa, Italy, Email: enrica.strettoi{at}in.cnr.it; or Dr. Brian D. Harfe at the above address, Email: bharfe{at}mgm.ufl.edu

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.

Key words: Dicer; miRNA; photoreceptors; bipolar cells; rosettes; horizontal cells; retinal degeneration; ERG

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Received Oct. 24, 2007; accepted March 17, 2008.

Correspondence should be addressed to either of the following: Dr. Enrica Strettoi, Istituto di Neuroscienze CNR, Via G. Moruzzi 1, 56100 Pisa, Italy, Email: enrica.strettoi{at}in.cnr.it; or Dr. Brian D. Harfe at the above address, Email: bharfe{at}mgm.ufl.edu

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