Novel roles for adenomatous polyposis coli family members and wingless signaling in cell adhesion and axon outgrowth during Drosophila brain development.

摘要

Mutation in the tumor suppressor gene, adenomatous polyposis coli (APC), leads to the initiation of colon cancer. Both Drosophila and mammals have two APC family members, APC1 and APC2. Our lab and others have characterized both Drosophila family members in the developing embryonic epidermis. In addition, we characterized the expression of both in the developing larval brain. Construction of the brain is one of the most complex developmental challenges. Wnt signals shape all tissues, including the brain, and the APC is a key negative regulator of Wnt/Wingless (Wg) signaling. We carried out the first assessment of the role of APC proteins in brain development, simultaneously inactivating both APC1 and APC2 in clones of cells in the Drosophila larval optic lobe. Loss of both APCs triggers dramatic defects in optic lobe development. Double mutant cells segregate from wild-type neighbors to form epithelial "loops", while double mutant neurons form tangled axonal "knots", suggesting changes in cell adhesion. Activation of Wg signaling downstream of APC mimics these phenotypes, a dominant-negative TCF construct blocks them, and a known Wg target, Decapentaplegic , is activated in double mutant clones. These results strongly suggest that the phenotypes result from activated Wg signaling. We also explored the roles of classic cadherins in differential adhesion. Finally, we propose a model suggesting that Wg signaling regulates fine scale cell fates along the anterior-posterior axis in the developing larval brain, in part by creating an adhesion gradient.