Cell cycle regulation and pattern formation in the Drosophila compound eye: Role of the retina aberrant in pattern (rap) gene

During the development of multicellular organisms, cell proliferation, cell growth and cell death are coordinated with cell fate specification and pattern formation. The timely exit of precursor cells from mitotic cell cycles is critical for proper development and pattern formation. The mechanisms that orchestrate the link between mitotic cell cycles and pattern formation are not well understood. In this dissertation I have used the development of the Drosophila compound eye as an experimental system to understand these mechanisms. My studies have focused on the rap ( retina aberrant in pattern) gene and its role in the development of the Drosophila compound eye. Analysis of the cellular pattern formation in rap loss-of-function mutants showed that in rap mutants photoreceptor neurons R1, R6 and R7 fail to differentiate. In addition, rap mutants have aberrant numbers of cone and pigment cells leading to altered retinal patterning. Examination of the mitotic pattern in the developing eye disc revealed that, in rap mutants, precursor cells failed to arrest at the G1 stage and underwent abnormal additional mitotic cycles. Some of the extra cells generated were eliminated by apoptosis. Molecular cloning and DNA sequence analyses revealed that rap encodes Fizzy-related (Fzr), a protein with WD (Trp-Asp) repeat domains. Rap/Fzr is a component of the Anaphase Promoting Complex (APC), a multi-protein ubiquitination complex involved in the timely degradation of mitotic cyclins. Results from the Rap/fzr expression studies are consistent with its role in cell cycle exit prior to cell fate specification. Loss-of-function mutations in rap/fzr show abnormal accumulation of cyclin B in the developing eye leading to additional mitotic cycles. Targeted overexpression of Rap/Fzr in the developing eye primordia using the GAL4-UAS system resulted in premature mitotic exit and either a drastic reduction or elimination of the eye. However, precocious mitotic exit did not inhibit neural differentiation. Differentiated neurons underwent endoreplication cycles giving rise to abnormally large cells and ectopic tumors. Interestingly, targeted expression of Rap/Fzr also resulted in the induction of ectopic antenna. These results suggest that Rap/Fzr plays a key role in the events leading to cell cycle exit and neuronal patterning in the developing eye.