ORGANIZATION OF APICAL CELL JUNCTIONS IN EYE

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DESCRIPTION (provided by applicant): Apico-basal cell polarity is essential for epithelial morphogenesis. Retinal differentiation involves dynamic process of cell-cell interactions and junctional organizations. The Drosophila compound eye provides an excellent gentic model for studying such cellular processes. A hallmark of photoreceptor differentiation is an explosive growth of the photosensitive organ, or rhabdomere, in the apical cell membrane. Drosophila Crumbs (Crb) protein plays a key role in organizing the rhabdomere and adherens junction (AJ) of photoreceptors. Our goal is to dissect the molecular basis of Crb function in the photoreceptor morphogenesis. Crb is a transmembrane protein with a short cytoplasmic tail. This intracellular domain (Crb intra) can recruit a MAGUK family protein Stardust (Sdt) and a PDZ domain protein Discs-lost (Dlt) to form a protein complex. An important function of Crb complex is to recruit AJs and to induce and/or maintain growth of rhabdomeres. Another conserved protein complex composed of Bazooka, Par6 and atypical PKC (aPKC) is critical for epithelial polarity. Interestingly, Par6 colocalizes and directly interacts with Dlt at the apical membrane. A novel Dlt homolog, Dlt-like (Dlk), also directly binds Par6. Therefore, it is proposed that Dlt and Dlk may regulate the cross-talk between the Crb and Par complexes. To test this hypothesis, the function of Crb and Par complexes in photoreceptor morphogenesis will be analyzed by genetic, molecular and cytochemical methods. Whether Dlt and Dlk are required for Crb and Par functions will be addressed. Specific interaction domains of Dlt and Dlk and their functions in the Par complex will be examined. In addition, specific proteins involved in trafficking of cytoskeletons to the Crb and Par complexes will be identified to understand the mechanism of AJ formation. Drosophila and human Crb proteins are conserved in structure and function. Human CRB1 is associated with retinal diseases including retinitis pigmentosa 12 and Leber Congenital Amaurosis. Therefore, studies on novel interaction of Crb and Par complexes will provide important insights into the mechanism of human CRB 1 in normal retinal development and diseases associated with CRB1 mutations.