The Jackson Laboratory, Bar Harbor, Maine, United States.
Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States.
Invest Ophthalmol Vis Sci. 2019 Aug 1;60(10):3283-3296. doi: 10.1167/iovs.18-26126.
Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma.
Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of genetic, biochemical, and immunofluorescence approaches.
URA identified Meox2 as a potential regulator of early gene expression changes in the optic nerve head (ONH) of DBA/2J mice. Meox2 haploinsufficiency did not affect the characteristic diseases of the iris or IOP elevation seen in DBA/2J mice but did cause a significant increase in the numbers of eyes with axon damage compared to controls. While young mice appeared normal, aged Meox2 haploinsufficient DBA/2J mice showed a 44% reduction in MEOX2 protein levels. This correlated with modulation of age- and disease-specific vascular and myeloid alterations.
Our data support a model whereby Meox2 controls IOP-dependent vascular remodeling and neuroinflammation to promote axon survival. Promoting these earliest responses prior to IOP elevation may be a viable neuroprotective strategy to delay or prevent human glaucoma.
青光眼是一种复杂的疾病，主要危险因素包括年龄增长和眼内压（IOP）升高。解析这些最早的事件可能会为治疗开辟新途径。此前，我们在 DBA/2J（D2）小鼠中进行了转录谱分析，D2 小鼠是一种广泛用于青光眼研究的小鼠模型。在此，我们利用这些数据来鉴定和测试 D2 型青光眼早期基因表达变化的调控因子。
采用 Ingenuity 通路分析中的上游调控因子分析（URA）来鉴定差异表达基因的潜在主要调控因子。通过遗传、生化和免疫荧光等方法组合，测试了一个假定调控因子-间质同源盒 2（Meox2）的功能。
URA 鉴定出 Meox2 是 D2 型小鼠视神经头（ONH）早期基因表达变化的潜在调控因子。Meox2 杂合不足并不影响 D2 型小鼠虹膜的特征性疾病或 IOP 升高，但与对照组相比，导致更多的眼睛出现轴突损伤。尽管年轻的小鼠看起来正常，但年龄较大的 Meox2 杂合不足的 D2 型小鼠的 MEOX2 蛋白水平降低了 44%。这与年龄和疾病特异性血管和髓样改变的调节有关。
我们的数据支持这样一种模型，即 Meox2 控制 IOP 依赖性血管重塑和神经炎症，以促进轴突存活。在 IOP 升高之前促进这些最早的反应可能是一种可行的神经保护策略，以延迟或预防人类青光眼。
