Looking for the Dark: Mature Drosophila larvae wander away from food and seek a dark site for pupation. While investigating this phenomenon Yamanaka et al. (p. 1113 ) found that four prothoracicotropic hormone (PTTH)–producing neurons mediate light preference in the central brain. PTTH circulates in the hemolymph and signals via its receptor, Torso, to two light sensors, sensitizing them for light detection. The larvae can then transform from wandering larvae into immobile pupae hidden from light and predatory eyes.

Adult size and fitness are controlled by a combination of genetics and environmental cues. In Drosophila, growth is confined to the larval phase and final body size is impacted by the duration of this phase, which is under neuroendocrine control. The neuropeptide prothoracicotropic hormone (PTTH) has been proposed to play a central role in controlling the length of the larval phase through regulation of ecdysone production, a steroid hormone that initiates larval molting and metamorphosis. Here, we test this issue by examining the consequences of null mutations in the ptth gene on Drosophila development. Loss of ptth causes several developmental defects including a delay in developmental timing, increase in critical weight, loss of coordination between body and imaginal disc growth, and reduced adult survival in sub-optimal environmental conditions like nutrition deprivation or high population density. We show that these defects are caused by a decrease in ecdysone production associated with altered transcription of ecdysone biosynthetic genes. Therefore, the PTTH signal contributes to proper coordination between various environmental cues and the developmental program to ensure individual fitness and survival.

The Drosophila adult male terminalia originate from the genital disc. During the pupal stages, the external parts of terminalia evert from two ventral stalks; the everted left and right dorsal halves fuse at the dorsal midline. At the same time the male terminalia perform a 360 clockwise rotation. Several mutations are known to affect the rotation of the male terminalia, while none is known to affect dorsal closure. We show here that the Pvf1 gene, encoding one of the three Drosophila homologues of the mammalian VEGF/PDGF growth factors, is required for both processes. Males either mutant for Pvf1 or bearing a dominant negative form of Pvr or stasis (stai), the unique PVF receptor, do not complete either rotation or dorsal closure. Pvf1 expression in the genital disc is restricted to the A8 cells. However, PVF1/PVR signaling influences A8, A9 and A10 cells, suggesting that the PVF1 protein diffuses from its source. Flies hemizygous for the apoptotic genes hid, reaper and grim, or mutant for puckered which encodes a phosphatase that down-regulates the n-Jun-N terminal kinase pathway, lead to the same phenotypes as mutations in PVF1/PVR. Our results indicate that PVF1/PVR signaling functions not only in apoptotic phenomena but are also required during rotation and dorsal closure of the Drosophila male genital disc.

Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke. Adaptation of cells to low oxygen (hypoxia) is a physiological response related to important diseases, including heart attacks, stroke, cancer, and diabetes. The mechanisms that mediate adaptation to hypoxia in humans are almost identical to those operating in diverse animal species, including mice, worms, and insects. The master regulator of cellular responses to hypoxia is a transcription factor named HIF, which induces a set of genes that mediate adaptation to oxygen starvation. Although it is known that regulation of HIF occurs mainly at the level of protein degradation and transcriptional coactivator recruitment, a comprehensive screen for HIF regulators has not been performed before. In this work, we have conducted an RNAi-based screen of the genome of the fruit fly Drosophila melanogaster, searching for genes that are required for HIF activity. This screen carried out in a cell culture system led to the definition of 30 critical regulators of HIF, most of which have not been associated with hypoxia biology before. The hits of the screen included components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. Our results open the possibility of performing detailed studies on HIF regulation that may lead to novel therapeutic strategies for important human diseases.