The regulation of tissue growth is of paramount importance for the understanding of vertebrate, including human, embryogenesis. It has also a tremendous medical significance. Deviations from normal tissue growth lead to severe patterning defects during embryogenesis, and to cancer in the mature organism. Abnormal patterns of cell proliferation produce a number of developmental eye disorders in humans. One of them is microphthalmia, which in the most extreme cases leads to the complete absence of eyes. To identify the genetic causes of human microphthalmia and anophthalmia, we chose to use an animal model, the zebrafish. Genetic screens in zebrafish identified many mutations that result in a decreased eye size. One of the most severe small eye phenotypes is caused by defects of the out of sight (out) locus. The goal of this project is to identify the molecular nature of the out gene, and to develop an understanding of its function on the cellular level. Once the molecular identity of this gene is known, we will investigate whether its defects are responsible for human microophthalmia by screeing DNA samples from diseased individuals. Similar animal model-based approaches have been very productive, leading to the identification of microphthalmia-causing mutations in several genes, including rx, six6, and sox2. This project is the first step on the way to use zebrafish mutants on a broader scale to identify the genetic causes of eye growth disorders. In the long run, the zebrafish is likely to become a major source of candidate genes to study this class of abnormalities. This strategy is likely to make a major contribution to the understanding of the genetic causes of microphthalmia and its more severe form, anophthalmia, in humans. We will use animal model, the zebrafish, to identify genes responsible for microphthalmia, a human eye disorder characterized by a reduction of eye size, and in the most extreme the absence of eyes. These studies will provide insight into the genetic basis of this debilitating disorder that affects 1 in 5,000 children. ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Greenwell, Thomas
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Massachusetts Eye and Ear Infirmary
United States
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den Hollander, Anneke I; Biyanwila, Janisha; Kovach, Peter et al. (2010) Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies. BMC Genet 11:102
Kitambi, Satish S; McCulloch, Kyle J; Peterson, Randall T et al. (2009) Small molecule screen for compounds that affect vascular development in the zebrafish retina. Mech Dev 126:464-77
Kitambi, Satish S; Malicki, Jarema J (2008) Spatiotemporal features of neurogenesis in the retina of medaka, Oryzias latipes. Dev Dyn 237:3870-81