Loss- and gain-of-function analyses of vacuolar protein sorting 2 in Notch signaling of Drosophila melanogaster

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Notch signaling is an evolutionarily conserved mechanism that controls many cell-fate specifications through local cell-cell interactions. The core mechanisms of Notch activation and its subsequent intracellular signaling are well understood. Various cellular functions are required for the activation and regulation of Notch signaling. Among them, the endocytosis of Notch and its ligands is important for the activation and suppression of Notch signaling. The endosomal sorting complex required for transport (ESCRT) proteins are required to sort ubiquitinated membrane proteins, such as Notch, into early endosomes. A loss-of-function allele of <i>vacuolar protein sorting 2</i> (<i>vps2</i>), which encodes a component of ESCRT-III, has been reported. However, this <i>vps2</i> mutant still produces the N-terminal half of the protein, and its phenotypes were studied in only a few organs. Here, we generated the first null mutant allele of <i>Drosophila vps2</i>, designated <i>vps2<sup>2</sup></i>, to better understand the function of this gene. In <i>Drosophila</i> wing imaginal discs homozygous for the <i>vps2<sup>2</sup></i> allele, early endosomes and multivesicular bodies (MVBs) were enlarged, and Notch and Delta accumulated inside them. As reported for the previous <i>vps2</i> mutant, the epithelium grew excessively under this condition. We further studied the roles of <i>vps2</i> by RNA interference-knockdown. These experiments revealed that a partial reduction of <i>vps2</i> attenuated Notch signaling; in contrast, the loss-of-function <i>vps2</i> mutant is reported to up-regulate the Notch signaling in eye imaginal disc cells. These results suggest that Notch signaling can be up- or down-regulated, depending on the level of <i>vps2</i> expression. Finally, we found that <i>vps2</i> overexpression also resulted in early-endosome enlargement and the accumulation of Notch and Delta. In these cells, a portion of the Vps2 protein was detected in MVBs and colocalized with Notch. These data indicate that the expression of <i>vps2</i> must be precisely regulated to maintain the normal structure of early endosomes.


  • Genes & Genetic Systems

    Genes & Genetic Systems 88(1), 45-57, 2013-02-25

    The Genetics Society of Japan

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