WTAP mediated m⁶A methylation modulates retinal photoreceptor function via facilitating of REEP6, PDE6B and RDH12...

Inherited retinal dystrophies (IRDs) are a leading cause of visual impairment and irreversible blindness worldwide, yet their precise molecular and genetic mechanisms remain unclear. N⁶-1ent. In the mammalian retina, m⁶A methylation is widely distributed in various cellular layers and is essential for retinal homeostasis. In this study, we assessed the in vivo roles of WTAP, a crucial component of the m⁶A methyltransferase complex, in the mammalian retina and demonstrated that loss of Wtap led to diminished scotopic ERG responses, progressive retinal degeneration, and significant loss of rod cells in mice. Wtap deficiency drastically reduced global m⁶A levels in the retina due to abolished WTAP-mediated stability of the methyltransferase complex. Mechanistically, absence of WTAP disrupts m⁶A modification of phototransduction-related genes and specifically causes the epigenetic silencing of PDE6B, REEP6, and RDH12. Detailed analysis further revealed that WTAP facilitated the translation of Reep6, Pde6b, and Rdh12 through modulating m⁶A deposition in 3'UTR of mRNAs. Moreover, reintroduction of WTAP in affected retinas, through crossing with CAG-Wtap mouse line or AAV-mediated gene therapy, partially restored expression of PDE6B, REEP6, and RDH12 and finally mitigated retinal degeneration. Collectively, our study highlights critical roles of WTAP in photoreceptor function and survival, thus providing novel therapeutic strategies for IRDs.