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On Mouse and Glaucoma
Simon John (Winner WGA-Award 2005)
The mouse is an important model system for determining molecular mechanisms of glaucoma
There remains much to learn about the molecular etiology of glaucoma
susceptibility. Understanding the molecular mechanisms that kill retinal
ganglion cells, and understanding the role elevated IOP and other risk
factors play in these processes will be important for designing new
treatments to prevent vision loss.
The mouse is an ideal mammalian model for deciphering complex
genetic interactions that underlie human glaucoma susceptibility.1-4
Glaucomatous mouse strains often develop glaucoma with a similar
age-related progression as humans and they do so in a relatively short
span of time (within 1 to 2 years). The mouse allows functional studies
in a highly controlled experimental setting.
The mouse is well suited for deciphering mechanism of
IOP elevation. The two types of outflow pathway present in humans,
conventional and uveoscleral, exist in mice. Both species have an
endothelial-lined canal of Schlemm (SC) and a trabecular meshwork (TM)
consisting of layers of well-organized trabecular beams covered with
endothelial-like trabecular cells. The biggest anatomic difference
between mice and humans is that mice have a poorly developed ciliary
muscle. Nevertheless, the prostaglandin analog Latanaprost lowers
mouse IOP as it does in humans and the effects of adenosine receptors on
IOP are similar between the two species.5,6 The documented
simi-
larities between mice and people in drainage structure anatomy, in
functional responses to drugs that inhibit aqueous production and
facilitate outflow, and in values for various outflow parameters
indicate that mice are a suitable models for studying IOP and its
glaucoma-associated elevation.
There are two classes of mouse models
relevant to glaucomatous neurodegeneration, experimentally induced
and inherited. The strength of experimentally induced glaucoma
models is the ability to induce chronic elevated IOP in genetically
manipulated mice at will, allowing relatively short-term experiments.
However, the induced neurodegeneration may have at least some mechanistic differences to inherited
glaucoma. Although experiments involving inherited forms of mouse
glaucoma are more time-consuming, the outcomes are more likely to
accurately model human glaucoma, which has a genetic component. Optic
nerve head excavation, a hallmark of human glaucoma, has been reported
for only the inherited models. I will now provide a few brief examples of how my laboratory is using mice to
understand glaucoma and suggest new treatments.
Primary congenital glaucoma (PCG) is a severe form of early onset
glaucoma. Many PCG cases are caused by recessive mutations in the
CYP1B1 gene.7,8 Striking phenotypic differences exist
between individuals with CYP1B1 mutations suggesting involvement
of further genes that modify the disease phenotype. Motivated by these
observations, we identified a modifier gene that alters the
phenotype in Cyp1b1 mutant mice.9 A mutant form of the
tyrosinase gene (Tyr) was identified as an enhancer of angle
dysgenesis. Cyp1b1 deficient mice that are also deficient for
Tyr have more severe angle malformations than do mice carrying the
Cyp1b1 mutation alone.9 Tyr also modified the
phenotype in Foxc1 deficient mice, another gene whose equivalent
in patients causes glaucoma. Tyrosinase produces L-DOPA and it
was found that administration of L-DOPA in the drinking water
substantially alleviated the developmental abnormalities of mice
deficient in both CYP1B1 and tyrosinase.9 These
experiments raise the pos-sibility that mutations in multiple genes
contributing to developmental glaucomas affect DOPA levels.10
They demonstrate the utility of mice for defining multifactorial genetic
interactions and for defining new pathways that are relevant to
glaucoma.
We also study an inherited glaucoma in DBA/2J mice. These mice
develop a pigmentary form of glaucoma characterized by a pigment
liberating iris disease, increased IOP and optic nerve degeneration.11
The degree of pigment dispersion and iris destruction in DBA/2J mice is
much greater than that observed in human patients with pigment
dispersion syndrome (PDS). This is likely explained by the discovery
that DBA/2J mice are mutant for two genes that can independently cause
disease but when inherited together interact to cause the severe DBA/2J
phenotype.12 In many human cases, PDS progresses to high IOP
and causes pigmentary glaucoma. However, a significant number of PDS
patients do not progress to high IOP. This implies that factors in
addition to direct obstruction by pigment are necessary to cause
sustained IOP elevation. It is likely that a genetic susceptibility
of the drainage tissues to a pigment/cell debris-induced pathology is
needed for glaucoma progression. Our mouse experiments provide strong
evidence for such inherited susceptibility. The DBA/2J mutations
have been introduced into a genetically different strain background. On
this new genetic background, these genes induce the iris disease but
there is rarely progression to high IOP or glaucoma.13 This
strongly suggests that genetic susceptibility factors determine the
likelihood of pigment dispersion progressing to elevated IOP, and these
mouse strains will allow the study and understanding of some of these
susceptibility factors.
DBA/2J glaucoma shows hallmarks of human glaucoma, including age-related variable progression of optic nerve atrophy in response to elevated IOP, asynchrony and optic nerve head excavation. In DBA/2 retinas with glaucoma, retinal ganglion cells and their axons are lost in 'fan-shaped' regions.14-16 The 'fan-shaped' areas of axon and cell loss are likely analogous to arcuate scotomas that occur in human glaucoma, since in the mouse the RGC axons do not curve across the retinal surface but radiate straight towards the optic nerve. Given these striking similarities, DBA/2 mice provide a valuable experimental system for deciphering molecular mechanisms of glaucomatous neurodegenertation, the effects of different risk factors, and for initially testing new treatments. Many groups are now using these mice for these purposes.
