Tissue-Specific Regulation of Vein/EGF Receptor Signaling in Drosophila

Abstract

Signaling by the Drosophila EGF receptor (DER) is modulated by four known EGF-like proteins: the agonists Vein (Vn), Spitz (Spi), and Gurken (Grk) and the antagonist Argos (Aos). DER is broadly expressed and thus tissue-specific regulation of ligand expression and activity is an important mechanism for controlling signaling. Here we investigate the tissue-specific regulation of Vn signaling by examining vn transcriptional control and Vn target gene activation in the embryo and the wing. The results show a complex temporal and spatial regulation of vn transcription involving multiple signaling pathways and tissue-specific activation of Vn target genes. In the embryo, vn is a target of Spi/DER signaling mediated by the ETS transcription factor PointedP1 (PntP1). This establishes a positive feedback loop in addition to the negative feedback loop involving Aos. The simultaneous production of Vn provides a mechanism for dampening Aos inhibition and thus fine-tunes signaling. In the larval wing pouch, vn is not a target of Spi/DER signaling but is expressed along the anterior-posterior boundary in response to Hedgehog (Hh) signaling. Repression by Wingless (Wg) signaling further refines the vn expression pattern by causing a discontinuity at the dorsal-ventral boundary. The potential for vn to activate DER target genes correlates with its roles in development: vn has a minor role in embryogenesis and does not induce DER target genes such as aos and pntP1 in the embryo. Conversely, vn has a major role in wing development and Vn/DER signaling is a potent inducer of DER target genes in the wing disc. Spi also has the potential to induce DER target genes in the wing disc. However, the ligands appear to evoke specific responses that result in different patterns of target gene expression. Finally, we show that other factors modulate the potential of Vn so that induction of Vn/DER target genes in the wing pouch is cell specific.

Sexually dimorphic regulation of the Wingless morphogen controls sex-specific segment number in Drosophila

“…4J). Wg and DER function cooperatively but antagonistically through complimentary expression to pattern developing tissues (43,44). Therefore, simultaneous misexpression of both Wg and vn may abrogate function of both signaling pathways.…”

Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells

“…55 In the same way, the stimulation of the HH cascade has been observed in Drosophilia to increase EGFR (DER) signaling by upregulating the expression of the EGFR ligand designated vein (vn), of which the mitogenic effect was essential for normal development. [56][57][58] Importantly, it has also been observed that the uncontrolled activation of SHH-GLI-1 signaling in the precursor cells was associated with the hyperproliferation and initiation of tumorigenesis of specific tumor types, including the brain and skin. 5,8,11,12 Although it still remains unclear whether the tumors derive from the aberrant activation of SHH-GLI-1 and EGF-EGFR in stem cells or progenitor cells or more differentiated cells, it appears that certain molecular interplay between these mitogenic cascades, which are prevalent during embryogenesis and morphogenesis in vertebrates and invertebrates, might also be manifested in certain cancer epithelial cells overexpressing these signaling elements.…”

A Novel Interaction Between hedgehog and Notch Promotes Proliferation at the Anterior–Posterior Organizer of the Drosophila Wing

“…vn is expressed in a stripe of anterior cells at the AP border (Wessells et al 1999) (Figure 9A), and in the third instar, the N ligand Dl is expressed in a pair of stripes near the AP border ( Figure 6A and Figure 9A). These Dl stripes mark the primordia that will produce vein 3 (in the anterior compartment) and vein 4 (in the posterior compartment; Figure 6, B-D; Figure 9A).…”

“…Hh signal transduction inhibits repressor formation and transforms Ci in the cytoplasmic complex to an active transcription factor (Ci Act ). Ci Act upregulates or induces expression of a number of target genes, including ptc, dpp, and vein (vn) (Basler and Struhl 1994;Tabata and Kornberg 1994;Schnepp et al 1996;Biehs et al 1998;Amin et al 1999); Vn is an EGF ligand (Wessells et al 1999). Dpp expressed in the band of Hh-receiving cells adjacent to the AP compartment border disseminates to target cells in both compartments (Lecuit et al 1996;Nellen et al 1996), and by regulating their proliferation and identity, embodies much of the functionality of the AP organizer.…”