Ythdf2 Ablation Protects Aged Retina From RGC Dendrite Shrinking and Visual Decline

Area of Science:

• Ophthalmology
• Molecular Biology
• Gerontology

Background:

• Aging-related vision loss and retinal degeneration are significant global health issues.
• Retinal ganglion cells (RGCs) are crucial for vision and susceptible to age-related damage.
• The m⁶A reader YTHDF2 was previously identified as a negative regulator of RGC dendrite development.

Purpose of the Study:

• To investigate the role of YTHDF2 in age-related retinal degeneration.
• To determine if YTHDF2 ablation protects against vision loss in aged mice.
• To identify potential YTHDF2 target genes involved in retinal protection.

Main Methods:

• Conditional knockout mouse models were used to ablate Ythdf2 in specific retinal cells.
• Retinal structure, RGC dendrite morphology, and visual function were assessed in aged mice.
• RNA sequencing and bioinformatics analyses were performed to identify YTHDF2 target mRNAs.

Main Results:

• Conditional ablation of Ythdf2 significantly protected the aged retina from RGC dendrite shrinking.
• Ythdf2 knockout mice exhibited preserved visual function compared to controls.
• Hspa12a and Islr2 were identified as potential YTHDF2 target mRNAs mediating these protective effects.

Conclusions:

• The m⁶A reader YTHDF2 plays a critical role in age-related retinal degeneration.
• Targeting YTHDF2 may offer a novel therapeutic strategy for combating age-related vision loss.
• YTHDF2-mediated regulation of Hspa12a and Islr2 contributes to retinal health during aging.