Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States.
https://orcid.org/0000-0001-7026-5790.
Invest Ophthalmol Vis Sci. 2024 May 1;65(5):15. doi: 10.1167/iovs.65.5.15.
Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFβ) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFβ signaling ameliorated ASD, supporting a role for the TGFβ pathway in disease pathogenesis. Here, we tested whether altered TGFβ signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice.
To test the role of TGFβ signaling in glaucoma-relevant phenotypes, we genetically reduced TGFβ signaling using mice with mutated Tgfbr2, which encodes the common receptor for all TGFβ ligands in Col4a1+/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry.
Col4a1+/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFβ receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1+/G1344D mice.
Our results suggest that elevated TGFβ signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.
编码 IV 型胶原α 1（COL4A1）和α 2（COL4A2）的基因突变导致多系统疾病，包括眼前段发育不良（ASD）和青光眼。我们之前表明，转化生长因子β（TGFβ）信号在 Col4a1 突变小鼠的发育前节中升高，并且降低 TGFβ 信号可改善 ASD，支持 TGFβ 途径在疾病发病机制中的作用。在这里，我们测试了改变的 TGFβ 信号是否也导致 Col4a1 突变小鼠的青光眼相关表型。
为了测试 TGFβ 信号在与青光眼相关的表型中的作用，我们使用 Tgfbr2 突变小鼠遗传降低了 TGFβ 信号，该基因编码所有 TGFβ 配体在 Col4a1+/G1344D 小鼠中的共同受体。我们进行了裂隙灯生物显微镜和光学相干断层扫描，用于定性和定量分析前节和后节，眼部组织和视神经的组织学分析，以及使用回弹眼压计评估眼内压。
Col4a1+/G1344D 小鼠表现出眼部排水结构的缺陷，包括虹膜角膜粘连，以及与青光眼神经退行性变一致的表型，包括神经纤维层变薄，视网膜神经节细胞丧失，视神经头凹陷和视神经变性。我们发现，降低 TGFβ 受体 2（TGFBR2）对 ASD 具有保护作用，改善了眼部排水结构缺陷，并预防了 Col4a1+/G1344D 小鼠的青光眼神经退行性变。
我们的结果表明，升高的 TGFβ 信号有助于 Col4a1 突变小鼠的青光眼神经退行性变。
