Conditional Knockouts of Interphotoreceptor Retinoid Binding Protein Suggest Two Independent Mechanisms for Retinal Degeneration and Myopia
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články
Grantová podpora
R01 EY004864
NEI NIH HHS - United States
R01 EY028859
NEI NIH HHS - United States
P30 EY006360
NEI NIH HHS - United States
I21 RX001924
RRD VA - United States
R01 DC009246
NIDCD NIH HHS - United States
I01 RX002806
RRD VA - United States
R01 EY021592
NEI NIH HHS - United States
R01 EY028450
NEI NIH HHS - United States
UL1 TR000454
NCATS NIH HHS - United States
T32 EY007092
NEI NIH HHS - United States
PubMed
38904640
PubMed Central
PMC11193143
DOI
10.1167/iovs.65.6.32
PII: 2793781
Knihovny.cz E-zdroje
- MeSH
- degenerace retiny * genetika metabolismus patofyziologie MeSH
- elektroretinografie * MeSH
- modely nemocí na zvířatech * MeSH
- myopie * genetika metabolismus patofyziologie MeSH
- myši inbrední C57BL MeSH
- myši knockoutované * MeSH
- myši MeSH
- oční proteiny * genetika metabolismus MeSH
- optická koherentní tomografie * MeSH
- proteiny vázající retinol * genetika MeSH
- retina metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- interstitial retinol-binding protein MeSH Prohlížeč
- oční proteiny * MeSH
- proteiny vázající retinol * MeSH
PURPOSE: Interphotoreceptor retinoid-binding protein's (IRBP) role in eye growth and its involvement in cell homeostasis remain poorly understood. One hypothesis proposes early conditional deletion of the IRBP gene could lead to a myopic response with retinal degeneration, whereas late conditional deletion (after eye size is determined) could cause retinal degeneration without myopia. Here, we sought to understand if prior myopia was required for subsequent retinal degeneration in the absence of IRBP. This study investigates if any cell type or developmental stage is more important in myopia or retinal degeneration. METHODS: IBRPfl/fl mice were bred with 5 Cre-driver lines: HRGP-Cre, Chx10-Cre, Rho-iCre75, HRGP-Cre Rho-iCre75, and Rx-Cre. Mice were analyzed for IRBP gene expression through digital droplet PCR (ddPCR). Young adult (P30) mice were tested for retinal degeneration and morphology using spectral-domain optical coherence tomography (SD-OCT) and hematoxylin and eosin (H&E) staining. Function was analyzed using electroretinograms (ERGs). Eye sizes and axial lengths were compared through external eye measurements and whole eye biometry. RESULTS: Across all outcome measures, when bred to IRBPfl/fl, HRGP-Cre and Chx10-Cre lines showed no differences from IRBPfl/fl alone. With the Rho-iCre75 line, small but significant reductions were seen in retinal thickness with SD-OCT imaging and postmortem H&E staining without increased axial length. Both the HRGP-Cre+Rho-iCre75 and the Rx-Cre lines showed significant decreases in retinal thickness and outer nuclear layer cell counts. Using external eye measurements and SD-OCT imaging, both lines showed an increase in eye size. Finally, function in both lines was roughly halved across scotopic, photopic, and flicker ERGs. CONCLUSIONS: Our studies support hypotheses that for both eye size determination and retinal homeostasis, there are two critical timing windows when IRBP must be expressed in rods or cones to prevent myopia (P7-P12) and degeneration (P21 and later). The rod-specific IRBP knockout (Rho-iCre75) showed significant retinal functional losses without myopia, indicating that the two phenotypes are independent. IRBP is needed for early development of photoreceptors and eye size, whereas Rho-iCre75 IRBPfl/fl knockout results in retinal degeneration without myopia.
Emory University Department of Ophthalmology Atlanta Georgia United States
Institute of Molecular Genetics of the ASCR Prague Czech Republic
Kirksville College of Osteopathic Medicine A T Still University Kirksville Missouri United States
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