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Programmed cell death (apoptosis) is a conserved process aimed to eliminate unwanted cells. The key molecules are a group of proteases called caspases that cleave vital proteins, which leads to the death of cells. In Drosophila , the apoptotic pathway is usually represented as a cascade of events in which an initial stimulus activates one or more of the proapoptotic genes ( hid, rpr, grim ), which in turn activate caspases. In stress-induced apoptosis, the dp53 ( Drosophila p53 ) gene and the Jun N-terminal kinase (JNK) pathway function upstream in the activation of the proapoptotic genes. Here we demonstrate that dp53 and JNK also function downstream of proapoptotic genes and the initiator caspase Dronc ( Drosophila NEDD2-like caspase) and that they establish a feedback loop that amplifies the initial apoptotic stimulus. This loop plays a critical role in the apoptotic response because in its absence there is a dramatic decrease in the amount of cell death after a pulse of the proapoptotic proteins Hid and Rpr. Thus, our results indicate that stress-induced apoptosis in Drosophila is dependant on an amplification loop mediated by dp53 and JNK. Furthermore, they also demonstrate a mechanism of mutual activation of proapoptotic genes.

Drosophila endocytosis-defective cells develop tumour overgrowths in the imaginal discs. We have analysed the tumorigenic potential of cells mutant for Rab5 , a gene involved in endocytosis. We found that while a compartment entirely made by Rab5 mutant cells can grow indefinitely, clones of Rab5 cells surrounded by normal cells are eliminated by cell competition. However, when a group of about 400 cells are simultaneously made mutant for Rab5 , they form an overgrowing tumour: mutant cells in the periphery are eliminated, but those inside survive and continue proliferating because they are beyond the range of cell competition. These results identify group protection as a mechanism to evade the tumour-suppressing function of cell competition in Drosophila . Furthermore, we find that the growth of the tumour depends to a large extent on the presence of apoptosis inside the tumour: cells doubly mutant for Rab5 and the proapoptotic gene dronc do not form overgrowing tumours. These results suggest that the apoptosis caused by cell competition acts as a tumour-stimulating factor, bringing about high levels of Jun N-terminal kinase and subsequently Wg/Dpp signalling and high proliferation levels in the growing tumour. We conclude that under these circumstances cell competition facilitates the progression of the tumour, thus reversing its normal antitumour role.

During the growth of Drosophila imaginal discs a process called ‘cell competition’ 1 eliminates slow-proliferating but otherwise viable cells. We report here that cell competition requires the function of the brinker ( brk ) gene, whose expression is normally repressed by Decapentaplegic (Dpp) signalling 2 , 3 , 4 but is upregulated in slow-growing Minute /+ cells. Excess brk expression activates the c-Jun amino-terminal kinase pathway, which in turn triggers apoptosis in these cells. We propose that slow-proliferating cells upregulate Brk levels owing to a disadvantage in competing for, or in transducing, the Dpp survival signal. This sequence of events might represent a general mechanism by which weaker cells are eliminated from a growing population, and might serve as a method of controlling cell number and optimizing tissue fitness and hence organ function.

Key Points Drosophila appendages (legs, antennae, mouthparts, analia, wings and halteres) arise from imaginal discs in specific segments. The critical event that permits embryonic cells to develop into the appendage primordia is expression of a homeobox gene called Distal-less ( Dll ). All imaginal discs subdivide into anterior and posterior compartments. The wing also subdivides into dorsal and ventral compartments in later stages in development. Cells at compartment borders produce morphogens — secreted signalling molecules such as hedgehog (Hh), wingless (Wg) and decapentaplegic (Dpp) — that pattern appendages by forming gradients. Cells respond to these morphogens by activating different patterns of gene expression, depending on the level of morphogen. Trunk cells become separated from appendage cells by mutual antagonism between Hh/Wg/Dpp at the centre of the disc, and the homeobox genes homothorax ( hth ) and extradenticle ( exd ), at the periphery. The response to the gradient of Wg and Dpp signals generates distinct genetic domains along the proximodistal axis of the appendage: high Wg and Dpp levels in the centre of the disc (which becomes the distal appendage) activate Dll , whereas moderate levels in the intermediate zone (which becomes the more proximal appendage) activate dachshund ( dac ). Appendage identity is specified by a combination of homeobox gene expression, which specifies the segment, and Dpp or Wg response genes, which specify dorsal or ventral properties. The mechanisms used in Drosophila to segregate the cells fated to form appendages and the genes involved are conserved in vertebrates. Just a glance at the body of the fruitfly Drosophila reveals that it has a main body part — the trunk — and a number of specialized appendages such as legs, wings, halteres and antennae. How do Drosophila appendages develop, what gives each appendage its unique identity, and what can the fruitfly teach us about appendage development in vertebrates?

To identify genes involved in the patterning of adult structures, Gal4-UAS (upstream activating site) technology was used to visualize patterns of gene expression directly in living flies. A large number of Gal4 insertion lines were generated and their expression patterns were studied. In addition to identifying several characterized developmental genes, the approach revealed previously unsuspected genetic subdivisions of the thorax, which may control the disposition of pattern elements. The boundary between two of these domains coincides with localized expression of the signaling molecule wingless.

The homeobox gene caudal (cad) has a maternal embryonic function that establishes the antero–posterior body axis of Drosophila 1 , 2 . It also has a conserved 2 , 4 late embryonic and imaginal function 1 related to the development of the posterior body region. Here we report the developmental role of cad in adult Drosophila . It is required for the normal development of the analia structures, which derive from the most posterior body segment. In the absence of cad function, the analia develop like the immediately anterior segment (male genitalia), following the transformation rule of the canonical Hox genes 5 . We also show that cad can induce ectopic analia development if expressed in the head or wing. We propose that cad is the Hox gene that determines the development of the fly's most posterior segment. cad acts in combination with the Hedgehog (Hh) pathway 6 to specify the different components of the analia: the activities of cad and of the Hh pathway induce Distal-less expression that, together with cad , promote external analia development. In the absence of the Hh pathway, cad induces internal analia development, probably by activating the brachyenteron and even-skipped genes.

In Drosophila, stresses such as x-irradiation or severe heat shock can cause most epidermal cells to die by apoptosis. Yet, the remaining cells recover from such assaults and form normal adult structures, indicating that they undergo extra growth to replace the lost cells. Recent studies of cells in which the cell death pathway is blocked by expression of the caspase inhibitor P35 have raised the possibility that dying cells normally regulate this compensatory growth by serving as transient sources of mitogenic signals. Caspase-inhibited cells that initiate apoptosis do not die. Instead, they persist in an \"undead\" state in which they ectopically express the signaling genes decapentaplegic (dpp) and wingless (wg) and induce abnormal growth and proliferation of surrounding tissue. Here, using mutations to abolish Dpp and/or Wg signaling by such undead cells, we show that Dpp and Wg constitute opposing stimulatory and inhibitory signals that regulate this excess growth and proliferation. Strikingly, we also found that, when Wg signaling is blocked, unfettered Dpp signaling by undead cells transforms their neighbors into neoplastic tumors, provided that caspase activity is also blocked in the responding cells. This phenomenon may provide a paradigm for the formation of neoplastic tumors in mammalian tissues that are defective in executing the cell death pathway. Specifically, we suggest that stress events (exposure to chemical mutagens, viral infection, or irradiation) that initiate apoptosis in such tissues generate undead cells, and that imbalances in growth regulatory signals sent by these cells can induce the oncogenic transformation of neighboring cells.

Vertebrate limbs grow out from the flanks of embryos, with their main axis extending proximodistally from the trunk. Distinct limb domains, each with specific traits, are generated in a proximal-to-distal sequence during development 1 . Diffusible factors expressed from signalling centres promote the outgrowth of limbs and specify their dorsoventral and anteroposterior axes 2 , 3 , 4 . However, the molecular mechanism by which limb cells acquire their proximodistal (P–D) identity is unknown 1 . Here we describe the role of the homeobox genes Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We find that Meis1/2 expression is restricted to a proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus 5 , and resembling the distribution of the Drosophila homologues homothorax ( hth ) 5 , 6 and extradenticle ( exd ) 7 ; that Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein; and that ectopic expression of Meis1 in chicken and hth in Drosophila disrupts distal limb development and induces distal-to-proximal transformations. We suggest that restriction of Meis1/Hth to proximal regions of the vertebrate and insect limb is essential to specify cell fates and differentiation patterns along the P–D axis of the limb.