ABSTRACT
The clathrin heavy chain is a fundamental element in endocytosis and therefore, in the internalization of several cell-surface receptors through which cells interact with their environment. Here we show that the only non-lethal mutant allele of the clathrin heavy chain identified to date in metazoans, the Drosophila Chc(4), involves the substitution of a residue at the knee region of the molecule that impairs clathrin-dependent endocytosis. We have investigated the consequences of this endocytic defect in Drosophila retinal development and found that it produces an inhibition of programmed cell death in the retinal lattice, followed by widespread death of interommatidial pigment cells once retinal development has been completed. Through genetic interactions and transgenic analyses, we show that Chc(4) phenotypes are caused by a Notch receptor gain-of-function, providing a dramatic example of the importance of Notch down-regulation by endocytosis. An increase in Notch signaling is also observed in Drosophila wings in response to the mutant clathrin, suggesting that Notch levels are controlled by clathrin-dependent endocytosis. We discuss the implications of these findings for current models on eye-development and for the role of endocytosis in Notch signaling.
Subject(s)
Cell Lineage , Down-Regulation , Drosophila melanogaster/cytology , Endocytosis , Photoreceptor Cells, Invertebrate/cytology , Receptors, Notch/metabolism , Retina/cytology , Amino Acid Sequence , Amino Acid Substitution , Animals , Apoptosis , Cell Survival , Clathrin Heavy Chains/genetics , Drosophila melanogaster/metabolism , Drosophila melanogaster/ultrastructure , Models, Biological , Molecular Sequence Data , Mutation/genetics , Phenotype , Photoreceptor Cells, Invertebrate/metabolism , Photoreceptor Cells, Invertebrate/ultrastructure , Protein Transport , Pupa/cytology , Receptors, Notch/chemistry , Retina/metabolism , Retina/ultrastructure , Subcellular Fractions/metabolism , Wings, Animal/metabolismABSTRACT
Morphogens are secreted signaling molecules which form spatial concentration gradients while moving away from a restricted source of production. A simple model of gradient formation postulates that the morphogens dilute as they diffuse between cells. In this review we discuss recent data supporting the idea that movement of the morphogen could also occur via vesicular trafficking through the cells. We explore the implications of these results for the control of gradient formation and the determination of the gradient slope which ultimately encodes the coordinates of positional information.
