Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities

Abstract

While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed.

Keywords: Axonal degeneration; DBA/2J; Genomics; IOP; Mouse genetics; Neurodegeneration; Neuroinflammation; Trabecular meshwork.

Figure 1. Glaucoma-relevant phenotypes that can be modeled and studied in mice

To study the cell biology of glaucoma, it is helpful to breakdown the disease into the individual events and/or phenotypes that can contribute to the disease. TM, trabecular meshwork; SC, Schlemm’s canal; CB, ciliary body; ONH, optic nerve head; RGC, retinal ganglion cell.

Figure 2. Tools available to study ocular disease in mice

There are many tools available to researchers using mice to study glaucoma-relevant phenotypes including: various imaging technologies, both advanced technologies which can only be used in model organisms and standard clinical imaging tools; physiological measurements to assess both anterior and posterior function; advanced cell biological analysis that can be used to probe the molecular mechanisms of glaucoma; mouse genetics, which can be used to discover new genes and molecular pathways underlying glaucoma and to critically test predicted pathways involved in glaucomatous pathophysiology; and numerous mouse models with glaucoma-relevant phenotypes that can be used to gain insight into human glaucoma. OCT, optical coherence tomography; IOP, intraocular pressure; RGC, retinal ganglion cell OMICs, genomics, proteomics and metabolomics; iPSCs, induced pluripotent stem cells; NTG, normal tension glaucoma; ASD, anterior segment dysgenesis; KI, knock in; KO, knock out; Cond, conditional allele; CRISPR, clustered regularly interspaced short palindromic repeats; TALEN, transcription activator-like effector nucleases; ZFN, xinc-finger nucleases; KOMP, knock out mouse project; EUCOMM, European Conditional Mouse Mutagenesis Program; MMRRC, Mutant Mouse Regional Resource Center; RI, recombinant inbred; CC, collaborative cross; DO, diversity outbred cross.

Figure 3. Ocular hypertension leads to numerous events in distinct subcompartments of RGCs that contribute to RGC loss in DBA/2J mice

DBA/2J mice have been used extensively to study the pathogenesis of ocular hypertension-induced RGC death. These studies have led to the idea that different cellular compartments of RGCs respond to ocular hypertension and that targeting these events can lessen RGC loss. This diagram assumes a critical early injury occurs to RGCs axons (axonal injury) in the optic nerve head. However, it is unclear (dashed lines) whether the initial driving event is an insult directly to the axons or through extrinsic means (the gray line is used to separate these potential early events to the later important event of axonal injury). Red boxes represent either pharmaceutical or genetic interventions that blocked a specific event in the degeneration cascade and have lessened RGC loss in DBA/2J mice.