Trends in Genetics
OpinionThe challenge of modeling macular degeneration in mice
Introduction
The first spontaneously arising inherited form of retinal degeneration in the mouse was identified in 1924 [1]; since then, arguably, the mouse has become the principal model organism for the study of this broad class of diseases [1]. Numerous spontaneously arising mouse strains harboring inherited retinal degenerations have been described 1, 2, and in many cases the gene causing the retinal degeneration has been identified (e.g. in the rd mouse) was found to have a defect in the gene Pde6b encoding a rod-specific cGMP phosphodiesterase [3]). With the ability to manipulate the mouse genome has come a surge in the use of mice to model retinal degenerative diseases 1, 2. For example, mouse models recapitulating the major symptoms of retinitis pigmentosa (RP), cone-rod dystrophies (CORD) and Leber's congenital amaurosis (LCA) have been created, resulting in a profound increase in our understanding of these and related diseases and providing a testing platform for various therapeutic interventions [2]. In humans RP is a disease that affects preferentially the rod-photoreceptor-rich peripheral retina, and CORD and LCA cause panretinal defects. Importantly, spontaneously arising mice with macular degeneration (MD) have not been identified. This is no great surprise because the mouse lacks a macula (see Glossary). As valuable as the mouse has been in modeling human retinal degenerative disease, the absence of a macula has caused some debate about the value of the mouse in studying this class of diseases [4].
Section snippets
Macular degeneration
MD is a disease of the outer retina characterized by damage to or loss of photoreceptors or retinal pigment epithelial (RPE) cells (or both) preferentially within the macula (Box 1; Figure 1), a specialized region at the center of the retina that provides the resolution necessary to read and drive. Those with MD typically experience a loss of high-resolution vision and perceive distortions or absence of images at the center of their visual field, progressing outward toward the periphery. This
Criteria for assessment of mouse models of macular degeneration
In general the vision science community has expected mouse models of MD to recapitulate the disease faithfully despite the absence of a macula. In this section we will establish a set of criteria for this ‘ideal’ model. In this, and the following sections, we will test existing mouse models of MD against these criteria, and determine whether we need to hold the mouse to these strict standards to gain significant understanding of the pathogenesis of MD.
The ideal model should recapitulate the
Mouse models of age-related macular degeneration
There are three genes that are considered to confer enhanced risk of or protection from AMD for which genetically altered mice have been studied. Those genes encode complement factor H (CFH) 10, 11, 12, 23, 24, fibulin-5 (FBLN5) [25] and apolipoprotein E (ApoE) 26, 27, 28. Although the Cfh gene has received a great deal of attention recently 10, 11, 12, development of a CFH AMD model is still in its infancy. The Cfh knockout mouse develops membranoproliferative glomerulonephritis [29]. The
Mouse models of inherited maculopathies
Because inherited maculopathies are caused by mutations in a single gene, many mice have been produced to study these diseases. The phenotypes of these diseases tend to be more consistent from patient to patient. We will next examine how well the mouse models of inherited maculopathies stand up to our ‘ideal’ criteria.
Sorsby's fundus dystrophy (SFD) is an autosomal dominant disorder caused by missense mutations in the gene TIMP3 (OMIM #136900). Transgenic mice that have the SFD-causative
Concluding remarks and future perspectives
Can we model MD in an organism that does not have a macula? Many mouse models already exist and we have gleaned a great deal of knowledge from them. In this sense we might never require an ‘ideal’ model. The many techniques available for manipulating the mouse genome and imaginatively crossing different genetically altered mice have enabled us to ask focused questions about how different genes such as ELOVL4 and ABCA4 cause related diseases, and how different retinal structures such as rod and
Acknowledgements
We are grateful to Benjamin Bakall and Catherine Bowes-Rickman for their critical reading of the manuscript; to Muna Naash for her comments on the manuscript and for sharing unpublished material; to Christine Curcio for critically reading the manuscript; and to Mathew LaVail for helpful discussions. Work in the authors’ laboratories is funded by the NIH (EY13160, EY13847, and EY14898), Phillip Morris USA and Phillip Morris International, the Macular Vision Research Foundation, and Research to
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