Zebrafish Mutants as Models for Congenital Ocular Disorders in Humans

Department of Biology, Texas AM eye; development; diseaseINTRODUCTIONInWesternsocieties,thevastmajorityofpeople( >68%)will experience some form of vision loss due to cataracts,glaucoma, or retinopathies such as age-related maculardegeneration and retinitis pigmentosa. Although manycauses of blindness throughout the world are preventable(e.g., poor nutrition, parasites), genetic disorders under-lie the majority of visual impairments in developedcountries. As these diseases exhibit simple to complexgenetic characteristics, the ability to develop therapiesthat prevent or correct vision loss will depend on a morethorough understanding of the genes and mechanismsinvolved in ocular dysfunction. To rapidly identify genesinvolved in blindness, researchers rely on model orga-nisms that mimic the physiology and pathology of thehuman eye and can be used for high-throughput geneticscreens. Recent advances demonstrate that the zebraﬁshserves as an ideal model for human ocular disorders.In this review, we focus exclusively on thoseidentiﬁed zebraﬁsh mutants that serve as models forinheritedformsofhumanblindness(Table1).Zebraﬁshmodels exist for human diseases affecting ocularmorphogenesis (coloboma), the anterior chamber (glau-coma and cataracts), as well as several types of photo-receptor disorders (Usher Syndrome, Bardet–BiedlSyndrome (BBS), achromotopsia, choroideremia, andretinitis pigmentosa). In many cases, the mutatedzebraﬁshgeneisanorthologtoaknownhumandiseasegene. Furthermore, of the dozens of zebraﬁsh mutantspresenting with ocular phenotypes, almost all arerepresented by only a single allele, which indicates weremain a long way from reaching saturation in geneticscreens. While some zebraﬁsh mutations may not yetcorrespond to known disease-causing loci in humans,analysis of these mutants will none the less provide abetter understanding of mechanisms leading to oculardysfunction and hopefully direct clinical geneticiststoward novel gene products or molecular pathwaysinvolvedinhumanocularpathologies.Asthepurposeofthisreviewistofocussolelyonmodelsofhumandisease,we refer readers to several recent reviews that describenumerous other zebraﬁsh mutations affecting differentaspects of eye development and function as well as themethodology to identify those mutants (Goldsmith andHarris,2003;TsujikawaandMalicki,2004b;MorrisandFadool, 2005).Development and Anatomy of the Zebraﬁsh EyeEye development in zebraﬁsh begins at the six-somitestage (SS) when the optic lobes evaginate from thediencephalon(SchmittandDowling,1994).Developmentisrapidthereafter;lensinductionoccursatthe14–15SS,the retina and retinal pigment epithelium (RPE)become morphologically distinct at 18–19 SS, choroidﬁssureformationbeginsat18SSandtheﬁssureclosesataround 24 hr post-fertilization (hpf). The ﬁrst post-mitotic neurons of the retina form at 28hpf (Hu andEaster, 1999; Schmitt and Dowling, 1999) and zebraﬁshexhibit visual function by 72hpf (Easter and Nicola,1996).Vertebrate eyes can be subdivided into an anteriorsegment composed of the cornea, lens, iris, ciliarybody, and other specialized tissues at the iridocornealangle, and a posterior segment composed of the retina,RPE, and choroid (Fig. 1). Anterior segment formationin embryonic and adult zebraﬁsh has been thoroughlydescribed (Soules and Link, 2005; Zhao et al., 2006;Dahm et al., 2007), and zebraﬁsh possess many stereo-typicalanteriorsegmentstructures.Theanatomyofthezebraﬁsh anterior segment differs to some extent fromthatinhumans;forinstance,thezebraﬁshlensdevelopsasasolidmassofcellsthatdelaminatefromthesurfaceectoderm,ratherthanasahollowvesicle.Zebraﬁshalsodo not possess iris muscles, instead, the zebraﬁsh iriscontainsseveraltypesofpigmentcellsthatmayfunctionin preventing light from entering the eye outside ofthe pupil (Soules and Link, 2005). Nonetheless, there is