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Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.

Veth KN, Willer JR, Collery RF, Gray MP, Willer GB, Wagner DS, Mullins MC, Udvadia AJ, Smith RS, John SW, Gregg RG, Link BA - PLoS Genet. (2011)

Bottom Line: Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes.This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis.Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

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Retinal cell density.Semi-thin plastic sections of the central retina, with associated quantification of cell density in each neural layer at 1 (A–B), 2 (C–D), and 6 (E–F) months in TL and bugeye. Scale bar A–E  = 50 µm. *p<0.05, ***p<0.001, t-test; FOV, field of view.
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pgen-1001310-g004: Retinal cell density.Semi-thin plastic sections of the central retina, with associated quantification of cell density in each neural layer at 1 (A–B), 2 (C–D), and 6 (E–F) months in TL and bugeye. Scale bar A–E  = 50 µm. *p<0.05, ***p<0.001, t-test; FOV, field of view.

Mentions: Histology suggested retinal cell density was affected in lrp2 mutant eyes (Figure 4). At 1 month, before eyes of mutant fish were visibly enlarged, there was a small reduction in retinal cell density as compared to wild-type fish (Figure 4A, 4B). By 2 months, when the onset of large eyes had occurred in some mutants but not in others, there was a significant difference in cell density in all layers of the retina (Figure 4C, 4D). As expected, at 6 months when relative eye size was greater overall, there was a further decrease in cell density (Figure 4E, 4F). When considering retinal cell density for each layer as a function of relative eye size (as measured by the ratio of the retinal cross-section length to body length), we found that for mutants, the relation between neuron density and relative eye size decreased in a linear manner (Figure 5A). The same was true when considering just the absolute size of eye (as measured by retinal cross-section length, Figure 5B). Interestingly, there was an increase in photoreceptor density in larger eyes for wild-type fish (Figure 5B). When considering cell density for wild-type and mutant eyes of the same absolute size, but of different ages in order to match size, density was still reduced in lrp2 mutant fish (Figure 5C). For this comparison we evaluated retinal cell density of 6-month old wild-type fish and 2-month old lrp2 mutant fish, each that had retinal lengths that fell between 2–3 mm. Importantly, there was no significant change in cell density for the retinal ganglion cells layer between 2–6 months in wild-type fish. For the inner nuclear and photoreceptor layers, there was a small, but significant change (ANOVA, p<0.001), where the cellular densities increased with age. Together, these data suggest that the reduced neuron density seen in lrp2 mutant retinas is not simply due to an acceleration of normal ocular growth.


Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.

Veth KN, Willer JR, Collery RF, Gray MP, Willer GB, Wagner DS, Mullins MC, Udvadia AJ, Smith RS, John SW, Gregg RG, Link BA - PLoS Genet. (2011)

Retinal cell density.Semi-thin plastic sections of the central retina, with associated quantification of cell density in each neural layer at 1 (A–B), 2 (C–D), and 6 (E–F) months in TL and bugeye. Scale bar A–E  = 50 µm. *p<0.05, ***p<0.001, t-test; FOV, field of view.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040661&req=5

pgen-1001310-g004: Retinal cell density.Semi-thin plastic sections of the central retina, with associated quantification of cell density in each neural layer at 1 (A–B), 2 (C–D), and 6 (E–F) months in TL and bugeye. Scale bar A–E  = 50 µm. *p<0.05, ***p<0.001, t-test; FOV, field of view.
Mentions: Histology suggested retinal cell density was affected in lrp2 mutant eyes (Figure 4). At 1 month, before eyes of mutant fish were visibly enlarged, there was a small reduction in retinal cell density as compared to wild-type fish (Figure 4A, 4B). By 2 months, when the onset of large eyes had occurred in some mutants but not in others, there was a significant difference in cell density in all layers of the retina (Figure 4C, 4D). As expected, at 6 months when relative eye size was greater overall, there was a further decrease in cell density (Figure 4E, 4F). When considering retinal cell density for each layer as a function of relative eye size (as measured by the ratio of the retinal cross-section length to body length), we found that for mutants, the relation between neuron density and relative eye size decreased in a linear manner (Figure 5A). The same was true when considering just the absolute size of eye (as measured by retinal cross-section length, Figure 5B). Interestingly, there was an increase in photoreceptor density in larger eyes for wild-type fish (Figure 5B). When considering cell density for wild-type and mutant eyes of the same absolute size, but of different ages in order to match size, density was still reduced in lrp2 mutant fish (Figure 5C). For this comparison we evaluated retinal cell density of 6-month old wild-type fish and 2-month old lrp2 mutant fish, each that had retinal lengths that fell between 2–3 mm. Importantly, there was no significant change in cell density for the retinal ganglion cells layer between 2–6 months in wild-type fish. For the inner nuclear and photoreceptor layers, there was a small, but significant change (ANOVA, p<0.001), where the cellular densities increased with age. Together, these data suggest that the reduced neuron density seen in lrp2 mutant retinas is not simply due to an acceleration of normal ocular growth.

Bottom Line: Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes.This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis.Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.

ABSTRACT
The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

Show MeSH
Related in: MedlinePlus