Semester

Summer

Date of Graduation

2003

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Peter H. Mathers.

Abstract

The homeobox was first identified as a common feature of Drosophila genes that control pattern formation during embryogenesis. These genes have been implicated in the regional specialization of the developing brain, spinal cord and other body structures. Homeobox gene families are highly conserved and encode DNA-binding regulatory proteins. Certain members of the homeobox gene family, including Pax6, Chx10, Lhx2, Otx2, Six3 and Six6, are crucial for development of the eye. A new family of retinal homeobox genes, Rx, is expressed early in embryogenesis in retinal stem cells. This expression pattern, along with results of overexpression and gene deletion studies, is consistent with a role for Rx in retinal stem cell specification and proliferation. In this dissertation, studies of the Rx expression in adult organisms reveal that Rx is abundantly expressed in human and mouse adult neural retina. A number of patients with anophthalmia and microphthalmia were screened and it was found that these conditions are associated with mutations in the Rx gene. The data generated in the first two projects raise a question about a role of Rx at different stages of eye development. To address this problem, a conditional allele of Rx gene was generated. This allele retains normal Rx activity but is a subject to inactivation by Cre recombinase. Using Cre recombinase under a control of forebrain-specific promoter (Foxg1 promoter), Rx conditional inactivation is achieved. Conditional animals (Rx-Foxg1-Cre) lack eyes and optic nerves but otherwise appear to be perfectly normal, making them an ideal model for anophthalmia as seen in the patient population. Analysis of Rx-Foxg1-Cre mice indicate that Rx is critical not only for the initial steps of eye development but also for axial patterning, since both, dorso-ventral and proximo-distal markers are affected.

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