Kaipa Balasankara Reddy, Kasetti Ramesh, Sundaresan Yogapriya, Li Linya, Yacoub Sam, Millar J Cameron, Cho William, Skowronska-Krawczyk Dorota, Maddineni Prabhavathi, Palczewski Krzysztof, Zode Gulab S
Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, and.
Department of Physiology and Biophysics, University of California Irvine School of Medicine, Irvine, California, USA.
JCI Insight. 2025 Jan 21;10(5):e188710. doi: 10.1172/jci.insight.188710.
Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking. We report the development and characterization of a new Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing the outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant loss of retinal ganglion cells (RGCs) and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437H mice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.
小梁网（TM）功能障碍导致眼内压（IOP）升高，进而引发神经退行性变，这是原发性开角型青光眼（POAG）的病理特征。轴突运输受损是青光眼性神经退行性变的早期关键特征。然而，一直缺乏能准确复制这些人类POAG特征的强大小鼠模型。我们报告了一种新的Cre诱导型小鼠模型的开发和表征，该模型表达人肌纤凝蛋白的DsRed标记的Y437H突变体（Tg.CreMYOCY437H）。单次玻璃体内注射HAd5-Cre可诱导TM中选择性MYOC表达，导致TM功能障碍，降低房水流出易度，并使Tg.CreMYOCY437H小鼠的IOP逐渐升高。持续的IOP升高导致Cre诱导的Tg.CreMYOCY437H小鼠视网膜神经节细胞（RGCs）显著丢失和进行性轴突变性。值得注意的是，在RGCs变性之前，在视神经乳头处观察到顺行轴突运输受损，且与年龄无关，这表明轴突运输受损导致了Tg.CreMYOCY437H小鼠的RGCs变性。相比之下，尽管RGCs大量丢失，但注射微珠的高眼压小鼠的轴突运输仍保持完整。我们的研究结果表明，Cre诱导型Tg.CreMYOCY437H小鼠复制了所有青光眼表型，为研究POAG中TM功能障碍和神经元丢失的早期事件提供了理想模型。
