ReviewMouse models of retinal ganglion cell death and glaucoma
Introduction
The past decade and a half has seen dramatic advances in the field of glaucoma research. A great deal of this explosion of knowledge can be attributed to the introduction of rodent models of experimental glaucoma, and the description of chronic inherited disease in inbred mice. Smaller rodent models have allowed access to glaucoma research by numerous research programs that before had neither the expertise nor financial clout to study this disease in the classic and still important non-human primate model.
A description of rat models of experimental glaucoma is given by several other contributions to this special issue (Johnson et al., 2009). These models have yielded tremendous new information on the cellular and molecular pathology of retinal ganglion cell death and optic nerve disease. Studies on mice, however, have one distinct advantage over rat studies, in that these animals enable researchers to conduct complex genetic manipulations in order to study the function of critical genes and biochemical pathways. This short review provides a description of current technologies that have been applied to mice to experimentally stimulate ganglion cell death or induce ocular hypertension. We also provide a discussion of various transgenic mice, and the DBA/2J mouse and associated substrains that naturally develop a form of pigmentary glaucoma with similar phenotypes to the human condition. Finally, we briefly touch on specific studies that have utilized genetic manipulations in mice to examine the roles of different genes in the ganglion cell death pathway, and have identified ganglion cell death susceptibility alleles.
Section snippets
Acute models of retinal ganglion cell death
Several methods of inducing rapid and relatively uniform retinal ganglion cell death, originally developed in animals with larger eyes, have been adapted for use in mice. These include direct intraocular injections of toxins that facilitate ganglion cell death such as staurosporine (Maass et al., 2007), or N-methyl-d-aspartate (NMDA), the non-hydrolyzable analog of glutamate (Li et al., 1999). NMDA injections were considered particularly relevant to the study of glaucoma during the 1990s when
Measurements of IOP in the mouse eye
IOP measurement is a necessary and important feature in any experiment employing murine glaucoma models. Both invasive and non-invasive methods have been employed, each with their advantages and disadvantages. Invasive methods include the use of manometric techniques in which a water-filled microneedle is attached to a pressure transducer, and servo-null systems in which a micropipette filled with electrolyte solution is inserted into the anterior chamber and changes in electrical resistance
Spontaneous glaucoma in the DBA/2J inbred strain of mice
In addition to inducible models of experimental glaucoma, some strains of mice have spontaneously developed mutations that result in chronic age-related glaucoma phenotypes (John, 2005). The most well characterized of these are the DBA/2J inbred line (John et al., 1998, Chang et al., 1999) and the related DBA/2NNia substrain (Sheldon et al., 1995, Danias et al., 2003b, Filippopoulos et al., 2006). DBA/2J mice are homozygous for mutations in two separate genes. The first is the b allele of
Spontaneous IOP elevation in other transgenic mice
Transgenic mice with targeted mutations in the α1 subunit of collagen type I (Col1a1r/r) develop spontaneous and gradual elevation of IOP (Aihara et al., 2003c). The mutations block matrix metalloproteinase (MMP) cleavage by coding for five amino acid substitutions adjacent to the site recognized by MMP-1, causing accumulation of collagen type I within aqueous outflow pathways and subsequent IOP elevation. At 24 weeks of age, IOPs in the Col1a1r/r transgenic mice were 23.5 ± 2.4 mmHg
Ganglion cell death and optic nerve degeneration
The ability to genetically alter mice to investigate gene function has helped to develop the concept that retinal ganglion cell death in glaucoma occurs as a series of compartmentalized self-destruct processes (Whitmore et al., 2005, Nickells, 2007). In this hypothesis, initial damage to the optic nerve axons leads first to the autonomous degeneration of the ganglion cell axon, and then, by virtue of impaired axonal transport, the apoptotic degeneration of the ganglion cell soma in the retina.
Acknowledgements
This work was supported by grant R01 EY01651 (SJM), R01 EY12223 (RWN) and CORE grants P30 EY005722 (DUMC) and P30 EY16665 (UWM) from the National Eye Institute, and unrestricted research grants from Research to Prevent Blindness provided to the Department of Ophthalmology and Visual Sciences (UWM) and the Department of Ophthalmology (DUMC).
References (83)
- et al.
Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18
Cell
(1985) - et al.
Programmed cell death of retinal ganglion cells during experimental glaucoma
Exp. Eye Res.
(1995) The optic nerve head in glaucoma: role of astrocytes in tissue remodeling
Prog. Retin. Eye Res.
(2000)- et al.
Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma
Am. J. Pathol.
(2005) - et al.
Effects of elevated intraocular pressure on mouse retinal ganglion cells
Vision Res.
(2005) - et al.
Transgenic studies on the role of optineurin in the mouse eye
Exp. Eye Res.
(2006) - et al.
Bax-dependent and independent pathways of retinal ganglion cell death induced by different damaging stimuli
Exp. Eye Res.
(2000) - et al.
Comparison of invasive and non-invasive tonometry in the mouse
Exp. Eye Res.
(2006) - et al.
A rat model of chronic pressure-induced optic nerve damage
Exp. Eye Res.
(1997) - et al.
Understanding mechanisms of pressure-induced optic nerve damage
Prog. Retin. Eye Res.
(2005)
From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma
Can. J. Ophthalmol.
Elevated amounts of myocilin in the aqueous humor of transgenic mice cause significant changes in ocular gene expression
Exp. Eye Res.
Tonopen measurement of intraocular pressure in mice
Exp. Eye Res.
Mouse model of sustained elevation in intraocular pressure produced by episcleral vein occlusion
Exp. Eye Res.
Response of motoneurons to neonatal sciatic nerve axotomy in Bax-knockout mice
Mol. Cell. Neurosci.
Sources of error with use of Goldmann-type tonometers
Surv. Ophthalmol
Glaucoma: thinking in new ways – a role for autonomous axonal self-destruction and compartmentalised processes?
Prog. Retin. Eye Res.
The bcl-2 protein family: arbiters of cell survival
Science
Reduction of intraocular pressure in mouse eyes treated with latanoprost
Investig. Ophthalmol. Vis. Sci.
Aqueous humor dynamics in mice
Investig. Ophthalmol. Vis. Sci.
Experimental mouse ocular hypertension: establishment of the model
Investig. Ophthalmol. Vis. Sci.
Ocular hypertension in mice with a targeted type I collagen mutation
Investig. Ophthalmol. Vis. Sci.
Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)
N. Engl. J. Med.
High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma
Proc. Natl. Acad. Sci. U.S.A.
GpnmbR150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma
BMC Genet.
Reliable measurement of mouse intraocular pressure by a servo-null micropipette system
Investig. Ophthalmol. Vis. Sci.
Noninvasive intraocular pressure measurements in mice by pneumotonometry
Investig. Ophthalmol. Vis. Sci.
The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves
BMC Neurosci.
Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma
J. Neurosci.
Long-term survival of retinal ganglion cells following optic nerve section in adult bcl-2 transgenic mice
Eur. J. Neurosci.
Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice
Nature Genet.
Measurement of intraocular pressure in awake mice
Investig. Ophthalmol. Vis. Sci.
Method for the noninvasive measurement of intraocular pressure in mice
Investig. Ophthalmol. Vis. Sci.
Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA/2NNia glaucomatous mice: comparison with RGC loss in aging C57BL/6 mice
Investig. Ophthalmol. Vis. Sci.
Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice
BMC Neurosci.
New perspectives on glaucoma
JAMA
Topographic and morphologic analyses of retinal ganglion cell loss in old DBA/2NNia mice
Investig. Ophthalmol. Vis. Sci.
A mouse model of elevated intraocular pressure: retina and optic nerve findings
Trans. Am. Ophthalmol. Soc.
Laser-induced mouse model of chronic ocular hypertension
Investig. Ophthalmol. Vis. Sci.
Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death
Nature
Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma
J. Cell Biol.
Cited by (159)
Novel glaucoma model in rats using photo-crosslinked azidobenzoic acid-modified chitosan
2021, Materials Science and Engineering CCommonalities of optic nerve injury and glaucoma-induced neurodegeneration: Insights from transcriptome-wide studies
2021, Experimental Eye ResearchCitation Excerpt :Glaucoma is a family of diseases affecting multiple biological systems, all of which result in the loss of RGCs and, if left untreated, blindness. There are purely genetic (inherited) models of glaucoma and experimentally induced models(Calkins, 2012; Geisert and Williams, 2020; Howell et al., 2008; McKinnon et al., 2009; Struebing and Geisert, 2015; Yang and Zack, 2011). Of the genetic models, the most widely used is the DBA/2J mouse.
Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium
2023, Molecular NeurodegenerationUrine-derived mesenchymal stem cells-derived exosomes enhances survival and proliferation of aging retinal ganglion cells
2023, BMC Molecular and Cell Biology