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<p>Inherited retinal dystrophies (IRDs) are a leading cause of visual impairment and irreversible blindness worldwide, yet their precise molecular and genetic mechanisms remain unclear. <i>N</i><sup>6</sup>-1ent. In the mammalian retina, m<sup>6</sup>A methylation is widely distributed in various cellular layers and is essential for retinal homeostasis. In this study, we assessed the <i>in vivo</i> roles of WTAP, a crucial component of the m<sup>6</sup>A methyltransferase complex, in the mammalian retina and demonstrated that loss of <i>Wtap</i> led to diminished scotopic ERG responses, progressive retinal degeneration, and significant loss of rod cells in mice. <i>Wtap</i> deficiency drastically reduced global m<sup>6</sup>A levels in the retina due to abolished WTAP-mediated stability of the methyltransferase complex. Mechanistically, absence of WTAP disrupts m<sup>6</sup>A 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 <i>Reep6, Pde6b</i>, and <i>Rdh12</i> through modulating m<sup>6</sup>A deposition in 3’UTR of mRNAs. Moreover, reintroduction of WTAP in affected retinas, through crossing with <i>CAG-Wtap</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Kuanxiang Sun,
  • Lin Zhang,
  • Wenjing Liu,
  • Can Chen,
  • Jiajie He,
  • Jinrui Cai,
  • Xiaoyan Jiang,
  • Yeming Yang,
  • Zhenglin Yang,
  • Xianjun Zhu

摘要

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.