Development and growth of the diverse parts of the eye must be perfectly coordinated in order to transmit correct visual images to the brain. The lens is responsible in part for coordinating eye growth but our knowledge about the underlying mechanisms is incomplete. This problem will be studied in Astyanax mexicanus, a teleost fish consisting of an eyed surface dwelling form (surface fish) and a blind cave-dwelling form (cavefish). Eye primordia are initially formed during cavefish development but they subsequently arrest and degenerate, resulting in a blind adult. The first tissue to degenerate is the lens, which is followed by the retina. Transplantation of a normal surface fish embryonic lens into a cavefish optic cup can restore a complete eye in adult cavefish. Several genes, including those encoding the anti-apoptotic protein 1A-crystallin, the heat shock protein Hsp901, and the midline signaling morphogen sonic hedgehog (shh) are candidates for regulators of cavefish lens apoptosis. The lens is also important in protecting the retina from apoptotic cell death and in the normal development of the cornea and sclera. The overall goal of this project is to determine how a lens becomes dysfunctional through apoptosis and how an abnormal lens in turn affects overall growth and development of the eye. The first two aims focus on events leading to apoptosis within the lens.
The first aim will investigate the role 1A-crystallin and 1B-crystallin downregulation in lens apoptosis.
The second aim will examine the role of hsp901 upregulation in lens apoptosis and its existence in a putative apoptotic pathway with shh and 1 -crystallin genes. The last two aims move outside the lens to focus on the retina, cornea and sclera, optic components whose development is dependent on the lens, and the retinal pigment epithelium (RPE), which may normally cooperate with the lens to protect the retina from apoptosis.
The third aim i nvestigates retinal genes that are potentially involved in the pathway controlling life or death of the retina, and the role of the lens in the differentiation and patterning of migratory neural crest cells responsible for cornea and sclera development.
The final aim will determine if the RPE collaborates with the lens in mediating retinal cell survival.
The aims of this application will combine lens microsurgical manipulations, the use of cellular and molecular markers, experimental gene overexpression and inhibition, and genetic analysis to create fish strains deficient in specific optic components that can be used to test hypothesis of eye growth coordination. This research is designed to provide new insights into how the lens coordinates eye growth and how blindness can result from defects in this process. This will fill a major gap in our understanding of both normal and abnormal eye development.

Public Health Relevance

Precise developmental coordination of the different parts of the eye is required to transmit a correct image to the brain. Using the blind cavefish as a model, this study is designed to provide new information about the role of the ocular lens in coordinating eye development. The results will provide insights into abnormal eye development.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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University of Maryland College Park
Schools of Earth Sciences/Natur
College Park
United States
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Herman, Adam; Brandvain, Yaniv; Weagley, James et al. (2018) The role of gene flow in rapid and repeated evolution of cave-related traits in Mexican tetra, Astyanax mexicanus. Mol Ecol 27:4397-4416
Yoshizawa, Masato; Robinson, Beatriz G; Duboué, Erik R et al. (2015) Distinct genetic architecture underlies the emergence of sleep loss and prey-seeking behavior in the Mexican cavefish. BMC Biol 13:15
Ma, Li; Jeffery, William R; Essner, Jeffrey J et al. (2015) Genome editing using TALENs in blind Mexican Cavefish, Astyanax mexicanus. PLoS One 10:e0119370
Espinasa, Luis; Bibliowicz, Jonathan; Jeffery, William R et al. (2014) Enhanced prey capture skills in Astyanax cavefish larvae are independent from eye loss. Evodevo 5:35
McGaugh, Suzanne E; Gross, Joshua B; Aken, Bronwen et al. (2014) The cavefish genome reveals candidate genes for eye loss. Nat Commun 5:5307
Ma, Li; Parkhurst, Amy; Jeffery, William R (2014) The role of a lens survival pathway including sox2 and ?A-crystallin in the evolution of cavefish eye degeneration. Evodevo 5:28
Yoshizawa, Masato; Jeffery, William R; van Netten, Sietse M et al. (2014) The sensitivity of lateral line receptors and their role in the behavior of Mexican blind cavefish (Astyanax mexicanus). J Exp Biol 217:886-95
Kowalko, Johanna E; Rohner, Nicolas; Rompani, Santiago B et al. (2013) Loss of schooling behavior in cavefish through sight-dependent and sight-independent mechanisms. Curr Biol 23:1874-83
O'Quin, Kelly E; Yoshizawa, Masato; Doshi, Pooja et al. (2013) Quantitative genetic analysis of retinal degeneration in the blind cavefish Astyanax mexicanus. PLoS One 8:e57281
Yoshizawa, Masato; O'Quin, Kelly E; Jeffery, William R (2013) Evolution of an adaptive behavior and its sensory receptors promotes eye regression in blind cavefish: response to Borowsky (2013). BMC Biol 11:82

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