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 ?A-crystallin, the heat shock protein Hsp90?, 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 ?A-crystallin and ?B-crystallin downregulation in lens apoptosis.
The second aim will examine the role of hsp90? upregulation in lens apoptosis and its existence in a putative apoptotic pathway with shh and ? -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 proposal 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. PROJECT NARRATIVE 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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014619-10
Application #
8305754
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2003-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$447,626
Indirect Cost
$149,209
Name
University of Maryland College Park
Department
Biology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
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
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
Hinaux, Helene; Poulain, Julie; Da Silva, Corinne et al. (2013) De novo sequencing of Astyanax mexicanus surface fish and Pachon cavefish transcriptomes reveals enrichment of mutations in cavefish putative eye genes. PLoS One 8:e53553
Kowalko, Johanna E; Rohner, Nicolas; Linden, Tess A et al. (2013) Convergence in feeding posture occurs through different genetic loci in independently evolved cave populations of Astyanax mexicanus. Proc Natl Acad Sci U S A 110:16933-8
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
Yoshizawa, Masato; Goricki, Spela; Soares, Daphne et al. (2010) Evolution of a behavioral shift mediated by superficial neuromasts helps cavefish find food in darkness. Curr Biol 20:1631-6
Jeffery, William R (2009) Chapter 8. Evolution and development in the cavefish Astyanax. Curr Top Dev Biol 86:191-221
Yamamoto, Yoshiyuki; Byerly, Mardi S; Jackman, William R et al. (2009) Pleiotropic functions of embryonic sonic hedgehog expression link jaw and taste bud amplification with eye loss during cavefish evolution. Dev Biol 330:200-11
Jeffery, William R (2008) Emerging model systems in evo-devo: cavefish and microevolution of development. Evol Dev 10:265-72
Yoshizawa, Masato; Jeffery, William R (2008) Shadow response in the blind cavefish Astyanax reveals conservation of a functional pineal eye. J Exp Biol 211:292-9

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