Scalloped (Sd) and Vestigial (Vg) are each needed for Drosophila wing development. We show that Sd is required for Vg function and that altering their relative cellular levels inhibits wing formation. In vitro, Vg binds directly to both Sd and its human homolog, Transcription Enhancer Factor-1. The interaction domains map to a small region of Vg that is essential for Vg-mediated gene activation and to the carboxy-terminal half of Sd. Our observations indicate that Vg and Sd function coordinately to control the expression of genes required for wing development, which implies that Vg is a tissuespecific transcriptional intermediary factor of Sd. Received August 24, 1998; revised version accepted November 3, 1998. The Drosophila vestigial (vg) and scalloped (sd) genes are expressed in similar patterns during wing development, and mutations in either gene lead to loss of wing tissue (Campbell et al. 1991(Campbell et al. , 1992Williams et al. 1991Williams et al. , 1993. Vg is a developmentally regulated nuclear protein of previously unknown function and is required principally for the development of the wing and haltere (Williams et al. 1991). Sd is part of a highly conserved family of transcription factors, the TEA/ATTS domain proteins and is an essential protein with a wider developmental role (Campbell et al. 1991(Campbell et al. , 1992.Expression of vg in cells of the developing wing primordia is established by a number of conserved signaling pathways and is required for subsequent cell proliferation and patterning. Expression of wingless (wg), as well as interactions between dorsal and ventral cells that activate the Notch receptor, initially directs limited vg expression along the dorsal-ventral (D/V) wing boundary (Williams et al. 1994;Kim et al. 1995Kim et al. , 1996; for review, see Irvine and Vogt 1997). Subsequent vg expression in the wing primordia occurs in response to both the D/V Wg signal and Decapentaplegic (Dpp), a member of the Transforming Growth Factor-␤ (TGF-␤) protein family, secreted by cells along the anterior-posterior (A/P) border. (Blair 1994;Kim et al. 1996Kim et al. , 1997Zecca et al. 1996;Neumann and Cohen 1997). By the late third larval instar, maximal amounts of Vg are seen in cells at the D/V wing disc boundary, whereas cells located farther from this border produce progressively less Vg (Williams et al. 1991). vg is also required to maintain sd expression in the wing progenitor cells, and sd is similarly required for the maintenance of elevated vg expression (Williams et al. 1993).A cellular role for Sd can be inferred from studies of its human homolog Transcription Enhancer Factor-1 (TEF-1). TEF-1 binds to SV40 enhancer sequences via a TEA/ ATTS class DNA-binding domain, and has been shown to require transcriptional intermediary factors (TIFs) for proper function (Xiao et al. 1991;Ishiji et al. 1992;Hwang et al. 1993;Gupta et al. 1997). Interestingly, it has been reported that the Sd TEA/ATTS domain does not bind the same enhancer DNA sequences in vitro as TEF-1, although TEF-1...

The innate immune response is critical for animal homeostasis and is conserved from invertebrates to vertebrates. This response depends on specialized cells that recognize, internalize, and destroy microbial invaders through phagocytosis. This is coupled to autonomous or non-autonomous cellular signaling via reactive oxygen species (ROS) and cytokine production. Lipids are known signaling factors in this process, as the acute phase response of macrophages is accompanied by systemic lipid changes that help resolve inflammation. We found that peroxisomes, membrane-enclosed organelles central to lipid metabolism and ROS turnover, were necessary for the engulfment of bacteria by Drosophila and mouse macrophages. Peroxisomes were also required for resolution of bacterial infection through canonical innate immune signaling. Reduced peroxisome function impaired the turnover of the oxidative burst necessary to fight infection. This impaired response to bacterial challenge affected cell and organism survival and revealed a previously unknown requirement for peroxisomes in phagocytosis and innate immunity.

Anti-mitotic agents such as paclitaxel and docetaxel are widely used for the treatment of breast, ovarian and lung cancers. Although paclitaxel induces apoptosis, this drug also modulates autophagy. How autophagy affects paclitaxel activity, is unclear. We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage. In mitotic cells, paclitaxel blocked activation of the class III phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel-treated cells, autophagosomes were generated but their movement and maturation was inhibited. Chemically or genetically blocking autophagosome formation diminished paclitaxel-induced cell death suggesting that autophagosome accumulation sensitized cells to paclitaxel toxicity. In line with these observations, we identified that primary breast tumors that expressed diminished levels of autophagy-initiating genes were resistant to taxane therapy, identifying possible mechanisms and prognostic markers of clinical chemotherapeutic resistance.

Many developing and adult tissues are comprised of polarized epithelia. Proteins that are asymmetrically distributed in these cells are thought to be localized by protein trafficking. Here we show that the distribution and function of the signaling protein Wingless is predetermined by the subcellular localization of its mRNA. High-resolution in situ hybridization reveals apical transcript localization in the majority of tissues examined. This localization is mediated by two independently acting elements in the 3' UTR. Replacement of these elements with non- or basolaterally localizing elements yields proteins with altered intracellular and extracellular distributions and reduced signaling activities. This novel aspect of the wingless signaling pathway is conserved and may prove to be a mechanism used commonly for establishing epithelial cell polarity.

Subdivision of the limb primordia into compartments initiates pattern formation in the developing limbs. Interaction between distinctly specific cells in adjacent compartments leads to localized expression of the secreted signalling molecules Wingless (Wg) or Decapentaplegic (Dpp), which in turn organize pattern and control growth of the limbs. The homeobox gene engrailed has been implicated in specification of posterior cell fate, whereas the LIM/homeobox gene, apterous, specifies dorsal fate. Removing apterous activity causes a complete transformation from dorsal to ventral fate and leads to the formation of an ectopic dorsal-ventral boundary organizer. By contrast, removing engrailed activity causes incomplete morphological transformation from posterior to anterior fate in the wing, and fails to produce an ectopic anterior-posterior organizer (reviewed in ref.2). Complete transformation can only be effected by simultaneously eliminating activity of engrailed and its homologue invected. Here we show that invected functions principally to specify posterior cell fate. Thus establishment of the anterior-posterior organizer and control of compartment identity are genetically distinguishable, and invected may perform a discrete subset of functions previously ascribed to engrailed.