Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma

Abstract

PURPOSE. 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. METHODS.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.RESULTS. 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 diseasespecific vascular and myeloid alterations. CONCLUSIONS.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.

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

“…Although sex could influence many other physiological or pathological events, we found that sex had no significant effects on the anatomical parameters of the inner retina measured in this study. Others have previously reported that there are sex-specific differences in retinal gene expression in mice, including in microglial and RGC-specific pathways 57 , and some glaucoma studies using mice have detected sex-specific differences in disease 58,59 -which would seemingly be unrelated to the traits we have studied.…”

The Contribution of Anterior Segment Abnormalities to Changes in Intraocular Pressure in the DBA/2J Mouse Model of Glaucoma: DBA/2J-Gpnmb+/SjJ Mice as Critical Controls

“…The DBA/2J mouse strain has been widely used as a model for ocular hypertension and glaucoma due to the presence of progressively worsening anterior chamber abnormalities and IOP increasing with age (Sheldon et al, 1995;Inman et al, 2006;Schlamp et al, 2006;Burroughs et al, 2011;Bosco et al, 2018;Mathieu et al, 2018;Buchanan et al, 2019;Jassim et al, 2019). In this study, we used strain-matched DBA/2J-Gpnmb + /SjJ mice to determine the relative contributions of corneal calcification and IPD to the apparent elevation of IOP characteristic of the DBA/2J mouse strain.…”

“…Experimental models of glaucoma are important to understanding the disease and identifying potential therapeutic strategies. The DBA/2J inbred mouse is one of the most widely used models of ocular hypertension-induced glaucoma and was first described as a model for glaucoma in 1995 (Sheldon et al, 1995;Inman et al, 2006;Schlamp et al, 2006;Burroughs et al, 2011;Bosco et al, 2018;Mathieu et al, 2018;Buchanan et al, 2019;Jassim et al, 2019). DBA/2J mice develop severe iris pigment dispersion (IPD), which causes elevated intraocular pressure (IOP) as a result of occluded aqueous humor drainage pathways (John et al, 1998;Libby et al, 2005;Scholz et al, 2008).…”