The Drosophila wing differentiation factor Vestigial–Scalloped is required for cell proliferation and cell survival at the dorso-ventral boundary of the wing imaginal disc

Abstract

Links between genes involved in development, proliferation and apoptosis have been difficult to establish. In the Drosophila wing disc, the vestigial (vg) and the scalloped (sd) gene products dimerize to form a functional transcription factor. Ectopic expression of vg in other imaginal discs induces outgrowth and wing tissue specification. We investigated the role of the VG-SD dimer in proliferation and showed that vg antagonizes the effect of dacapo, the cyclin-cdk inhibitor. Moreover, ectopic vg drives cell cycle progression and in HeLa cultured cells, the VG-SD dimer induces cell proliferation per se. In Drosophila, ectopic vg induces expression of dE2F1 and its targets dRNR2 and string. In addition vg, but not dE2F1, interacts with and induces expression of dihydrofolate reductase (DHFR). Moreover, a decrease in VG or addition of aminopterin, a specific DHFR inhibitor, shift the dorso-ventral boundary cells of the disc to a cell death sensitive state that is correlated with reaper induction and DIAP1 downregulation. This indicates that vg in interaction with dE2F1 and DHFR is a critical player for both cell proliferation and cell survival in the presumptive wing margin area.

Control of growth and positional information by the graded vestigial expression pattern in the wing of Drosophila melanogaster

“…(18) or sd (25) expression grow poorly (3-5 cells) and disappear from the wing blade 24 h after clone initiation (data not shown). This finding indicates that vg expression is formally required for the survival of wing blade cells (1,20). The cell survival and growth of mutant cells for vg were not favored in a Minute (M) genetic background either, dying quickly as it happens in a WT background (data not shown).…”

“…vg is symmetrically expressed from early larval development in both sides of D͞V boundary, integrating inputs from the A͞P (dpp signaling) and D͞V (wg and N signaling) axes of growth (17)(18)(19). Recent reports (1,20) have shown that the lack of function of the Vg-Sd complex prevents the development of the wing blade, affecting cell survival in distal wing territories. Unlike the lack of function of the Vg-Sd complex, the overexpression in vivo (1,14,18,(21)(22)(23) or in cell culture (1) can promote cell proliferation.…”

“…Unlike the lack of function of the Vg-Sd complex, the overexpression in vivo (1,14,18,(21)(22)(23) or in cell culture (1) can promote cell proliferation. These data have suggested that the Vg-Sd complex stimulate cell proliferation per se, in a constitutive manner (1).…”

“…Both parameters result from the coordination of cell proliferation, cell death, and arrangement of cells in specific patterns. During the last decades, our knowledge regarding the genetic basis of the cell cycle and cell survival has been greatly advanced, but the systemic relationships between gene expression patterns in cells and their proliferation only now are beginning to be established (1)(2)(3)(4)(5).…”

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

“…We speculate that TEAD may have a role in YAP function. Interestingly, Scalloped, the Drosophila TEAD homolog, plays some roles in regulating cell proliferation and apoptosis (Delanoue et al 2004), suggesting an intriguing possibility of Scalloped as a Yki target transcription factor. The bantam microRNA plays a critical role in Drosophila to mediate the Hippo pathway signaling, but there is no obvious bantam homolog in human genome ; Thompson and Cohen 2006).…”