Conditional Knockouts of Interphotoreceptor Retinoid Binding Protein Suggest Two Independent Mechanisms for Retinal Degeneration and Myopia

. 2024 Jun 03 ; 65 (6) : 32.

Jazyk angličtina Země Spojené státy americké Médium print

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid38904640

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

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.

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