Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
ReviewUsing zebrafish to study the complex genetics of glaucoma☆
Section snippets
Genes involved in glaucoma
FOXC1 (previously named FKHL7, FREAC3 and MF1) is a forkhead transcription factor, named for its 3 looped helices that form a winged domain known to mediate protein–DNA interactions. FOXC1 is highly expressed in the periocular mesenchymal cells that contribute to the anterior segment during development. FOXC1 is also expressed at lower levels in the adult anterior segment. Mutations in FOXC1 result in several ASDs including Axenfeld-Reiger Syndrome and iridogoniodysgenesis anomaly Berry et al.,
Using zebrafish to study glaucoma
The use of transgenic mice has proven to be extremely valuable in describing the function of genes critical for formation of the anterior segment. However, the practicality of the mouse model becomes limited when faced with identifying the complex genetic interactions that underlie conditions such as glaucoma. In order to identify and study multi-gene causative loci as well as important modifying loci for glaucomas, a relevant model with powerful forward and reverse capabilities is required.
LMX1B: a case study
Based on previous experiments, we can hypothesize many possibilities for how mutations that affect development of the anterior segment contribute to glaucoma. First, anatomical alterations in some cases may adversely affect aqueous humor drainage structures and promote elevated IOP. However, it is also important to determine how mutations in other developmentally significant genes, such as LMX1B, might contribute to glaucoma in the absence of defects in the anatomy of the anterior segment. As
Summary
Despite our knowledge of numerous genes now implicated in glaucoma, our understanding of the complexities of the genetics behind the disease is still quite incomplete. Observations in both humans and mice strongly suggest that multiple genes interact to cause and affect the progression of glaucoma. As a next step to better understand glaucoma, it is of critical importance that the interacting loci are identified and characterized. Human diseases involving multiple gene loci call for a relevant
Acknowledgements
We gratefully acknowledge Simon S.W. John and Richard S. Smith (HHMI and The Jackson Labs, Bar Harbor, MN) for helpful discussions. Outstanding technical assistance was provided by Michael Cliff and Melissa Reske. Financial support was provided by NIH grants T32-EY014537 (CM); R01EY013606 (ES) and 1RO1EY014167 (BL); a Prevent Blindness America Grant (BL); a Basil O'Connor Fellowship Grant (BL); and a Glaucoma Foundation Grant (BL).
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Cited by (53)
Zebrafish anterior segment mesenchyme progenitors are defined by function of tfap2a but not sox10
2023, DifferentiationCitation Excerpt :One of the tissue types derived from POM are the ASM. Any disruption in the specification or migration of POM or ASM cells can give rise to AS dysgenesis (ASD) phenotypes and disorders (Akula et al., 2018; Gould et al., 2004; McMahon et al., 2004; Reis LaS, 2011). ASD is an umbrella term for maldevelopment of the AS including the cornea, lens, iridocorneal angle (ICA) and iris and includes several congenital conditions.
Zebrafish as a model for developmental biology and toxicology
2018, Handbook of Developmental NeurotoxicologyAnalysis of the retina in the zebrafish model
2016, Methods in Cell BiologyCitation Excerpt :This can be, however, expensive in vertebrate model organisms, such as mice, due to long generation time and large population sizes involved. The zebrafish is thus an attractive model to identify the genetic causes of complex traits such as glaucoma, through IOP measurements in different mutant backgrounds (McMahon, Semina, & Link, 2004). IOP measurements in zebrafish are accomplished with the use of SNMS (servo-null micropipette system), a classic technique developed to measure hydrostatic pressures in structures too small for conventional pressure measuring devices (Avila, Carré, Stone, & Civan, 2001).
Glaucoma
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsToward a better understanding of human eye disease: Insights from the zebrafish, Danio rerio
2011, Progress in Molecular Biology and Translational ScienceCitation Excerpt :Despite this difference, the overall similarities in aqueous humor outflow tissue structure make the zebrafish a potentially valuable model organism for human glaucomas. The zebrafish is an ideal model system in which to study multigenic traits.279 In addition, methodology for measuring zebrafish IOP has been developed, and average intraocular pressure ranges are similar in mammals and zebrafish.152
Mutations at key pore-lining positions differentiate the water permeability of fish lens aquaporin from other vertebrates
2010, FEBS LettersCitation Excerpt :This can have intriguing consequences in the physiology of fish vision as compared to air-living organisms and should be kept in mind when using fish models as tools for understanding the biology of visual disorders in humans [21,22].
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This paper is based on a presentation given at the conference: Aquatic Animal Models of Human Disease hosted by the American Type Culture Collection and the University of Miami in Manassas, Virginia, USA, September 29–October 2, 2003.