WT and DN-Kuz border cells,

image courtesy of Denise Montell, John Hopkins School of Medicine, Baltimore.

During Drosophila melanogaster oogenesis, Notch signalling is required for several processes including follicle cell differentiation and border cell migration. However, the mechanisms that regulate Notch activity are poorly understood. Denise Montell and colleagues reveal a novel mechanism of Notch activation by showing that the metalloproteinase Kuzbanian (Kuz) cleaves and activates Notch specifically in border cells.

Notch is synthesized as a transmembrane precursor and its activity is known to be regulated by glycosylation, proteolytic cleavage, endocytosis and trafficking. During follicle cell differentiation increased levels of the Notch ligand Delta and the glycosyltransferase Fringe (that increases the affinity of Notch for Delta) regulate Notch activity. By contrast, during border-cell migration, which takes place at a later stage in development, Delta is uniformly expressed indicating that a different mechanism of Notch activation is involved.

Montell and colleagues identified Kuz in a previous study using a genome-wide screen for genes that are upregulated in migrating border cells. Conditional expression of a dominant negative form of Kuz (DN-Kuz) in border cells strongly inhibits their migration towards the oocyte. The authors now show that expression of the intracellular domain of Notch rescues the migration defect of DN-Kuz border cells, indicating that Notch is a substrate for Kuz in these cells. In agreement with these results, they also found that during border cell migration, Notch activity was specifically restricted to the migratory population of border cells and that Kuz was required for the spatially-localized pattern of Notch activity. Expression of DN-Kuz does not affect border-cell differentiation, but specifically affects their morphology; border cell clusters appear less rounded and the cells are less tightly grouped.

This paper demonstrates that Kuz, Notch and Delta are required for border cell migration (border cells in Delta mutants also fail to migrate) and that different mechanisms regulate Notch activity during D. melanogaster oogenesis. The potential involvement of other Kuz substrates in border cell migration and the precise signalling pathway that induces cell motility downstream of Notch remain to be investigated.

Author: Monica Hoyos-Flight