Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila

SUMMARYAggressive neoplastic growth can be initiated by a limited number of genetic alterations, such as the well-established cooperation between loss of cell architecture and hyperactive signaling pathways. However, our understanding of how these different alterations interact and influence each other remains very incomplete. Using Drosophila paradigms of imaginal wing disc epithelial growth, we have monitored the changes in Notch pathway activity according to the polarity status of cells and show that epithelial polarity changes directly impact the transcriptional output of the Notch pathway. Importantly, we show that this Notch pathway redirection is not mediated by a redeployment of Su(H), the Notch dedicated transcription factor, but relies on the cooperation with a combination of oncogenic transcription factors. Our work highlights in particular the role of the stress response CEBPG homologue CG6272/Irbp18 and of its partner Xrp1 suggesting that parts of the cellular competition program might promote neoplastic growth.

Configurational forces for growth and shape regulations in morphogenesis

Morphogenetic theories investigate the mechanisms of creation and regulation of definite biological forms in living organisms. The incredible diversity of shapes and sizes is generated through a barely unknown coordination of biochemical processes occurring at molecular levels. Such a crosstalk not only defines the rules of a robust scheme of matter differentiation, but it also has the capacity to adapt with respect to some variations of the environmental conditions. In this work, we propose a continuum model of growth and mass transport for biological materials during morphogenetic processes. Using the theory of configurational forces, we define the thermomechanical bases for understanding how both the mechanical and the biochemical states can orchestrate growth. The model is successfully applied to describe the morphogen-driven growth control in the imaginal wing disc of Drosophila melanogaster.

Connecting Hh, Dpp and EGF signalling in patterning of theDrosophilawing; the pivotal role ofcollier/knotin the AP organiser

Hedgehog (Hh) signalling from posterior (P) to anterior (A) cells is the primary determinant of AP polarity in the limb field in insects and vertebrates. Hh acts in part by inducing expression of Decapentaplegic (Dpp), but how Hh and Dpp together pattern the central region of the Drosophila wing remains largely unknown. We have re-examined the role played by Collier (Col), a dose-dependent Hh target activated in cells along the AP boundary, the AP organiser in the imaginal wing disc. We found that col mutant wings are smaller than wild type and lack L4 vein, in addition to missing the L3-L4 intervein and mis-positioning of the anterior L3 vein. We link these phenotypes to col requirement for the local upregulation of both emc and N, two genes involved in the control of cell proliferation, the EGFR ligand Vein and the intervein determination gene blistered. We further show that attenuation of Dpp signalling in the AP organiser is also col dependent and, in conjunction with Vein upregulation, required for formation of L4 vein. A model recapitulating the molecular interplay between the Hh, Dpp and EGF signalling pathways in the wing AP organiser is presented.

Dpp signalling is a key effector of the wing-body wall subdivision of theDrosophilamesothorax

During development, the imaginal wing disc of Drosophila is subdivided along the proximal-distal axis into different territories that will give rise to body wall (notum and mesothoracic pleura) and appendage (wing hinge and wing blade). Expression of the Iroquois complex (Iro-C) homeobox genes in the most proximal part of the disc defines the notum, since Iro-C– cells within this territory acquire the identity of the adjacent distal region, the wing hinge. Here we analyze how the expression of Iro-C is confined to the notum territory. Neither Wingless signalling, which is essential for wing development, nor Vein-dependent EGFR signalling, which is needed to activate Iro-C, appear to delimit Iro-C expression. We show that a main effector of this confinement is the TGFβ homolog Decapentaplegic (Dpp), a molecule known to pattern the disc along its anterior-posterior axis. At early second larval instar, the Dpp signalling pathway functions only in the wing and hinge territories, represses Iro-C and confines its expression to the notum territory. Later, Dpp becomes expressed in the most proximal part of the notum and turns off Iro-C in this region. This downregulation is associated with the subdivision of the notum into medial and lateral regions.

DRacGAP, a novel Drosophila gene, inhibits EGFR/Ras signalling in the developing imaginal wing disc

We have identified a novel Drosophila gene, DRacGAP, which behaves as a negative regulator of Ρ-family GTPases DRac1 and DCdc42. Reduced function of DRacGAP or increased expression of DRac1 in the wing imaginal disc cause similar effects on vein and sensory organ development and cell proliferation. These effects result from enhanced activity of the EGFR/Ras signalling pathway. We find that in the wing disc, DRac1 enhances EGFR/Ras-dependent activation of MAP Kinase in the prospective veins. Interestingly, DRacGAP expression is negatively regulated by the EGFR/Ras pathway in these regions. During vein formation, local DRacGAP repression would ensure maximal activity of Rac and, in turn, of Ras pathways in vein territories. Additionally, maximal expression of DRacGAP at the vein/intervein boundaries would help to refine the width of the veins. Hence, control of DRacGAP expression by the EGFR/Ras pathway is a previously undescribed feedback mechanism modulating the intensity and/or duration of its signalling during Drosophila development.