Vertebrate lens is a model system for understanding processes such as tissue induction and organ development. Our knowledge about lens development is largely based on tissue studies or morphological analyses in the chick and mouse. These basic processes are conserved in the developing human lens and many genetic diseases affecting the anterior segment of the human eye are pertubations in the development or maintenance of these structures. Unfortunately, development of the vertebrate lens primarily occurs in utero, making molecular and genetic analyses difficult. However, the translucent zebrafish embryo develops externally, which simplifies the visualization of organ development and the isolation of tissue for molecular analyses. This proposal will analyze the molecular basis for vertebrate lens development using wild-type and mutant zebrafish. Several zebrafish lens mutants were identified in a chemical mutagenesis screen and this proposal focuses on the molecular characterization of the arrested lens (arl) mutant. The arl mutant arrests development at the lens vesicle stage and displays aphakia at 5 days post-fertilization. We will examine if this developmental arrest is due to the termination of cell proliferation or increased cell death. We will also examine the extent of lens cell differentiation by studying the temporal and spatial expression patterns of the zebrafish c-Maf and [alpha]B-crystallin genes during wild-type and arl mutant lens development. In addition, because mutations in Pitx3 and Foxe3 cause lens vesicle defects in mouse and humans, the zebrafish homologs of these genes will be cloned and characterized in wild-type and mutant lenses. Finally, the arl mutation will be mapped by linkage to simple sequence length polymorphisms (SSLPs) and the arl gene will be positionally cloned. The characterization of the molecular phenotype and determination of the underlying arl gene defect will lead to the identification of candidate genes in humans causing anterior segment dysgenesis and cataracts.
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| Shi, Xiaohai; Luo, Yiying; Howley, Sinead et al. (2006) Zebrafish foxe3: roles in ocular lens morphogenesis through interaction with pitx3. Mech Dev 123:761-82 |
| Smith, Amber A; Wyatt, Keith; Vacha, Jennifer et al. (2006) Gene duplication and separation of functions in alphaB-crystallin from zebrafish (Danio rerio). FEBS J 273:481-90 |
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| Vihtelic, Thomas S; Yamamoto, Yoshiyuki; Springer, Sandra S et al. (2005) Lens opacity and photoreceptor degeneration in the zebrafish lens opaque mutant. Dev Dyn 233:52-65 |
| Shi, Xiaohai; Bosenko, D V; Zinkevich, N S et al. (2005) Zebrafish pitx3 is necessary for normal lens and retinal development. Mech Dev 122:513-27 |
