Mutations in rugose promote cell type-specific apoptosis in the Drosophila eye

Abstract

rugose (rg) encodes an A kinase anchor protein and was isolated as a genetic interactor of the Notch and epidermal growth factor receptor (EGFR) pathways during eye development in Drosophila. rg mutants display a small, rough eye phenotype primarily caused by the loss of cone cells. Here we show that the basis of this phenotype is cell type-specific apoptosis rather than transformation and hence can be rescued by reduction of proapoptotic signals. Moreover, a nearly complete rescue is observed by an increased Notch signal suggesting an antiapoptotic function of Notch in this developmental context. Cone cell loss in rg mutants is accompanied by enhanced Jun N-terminal kinase activity and, concomitantly, by a reduction of EGFR signalling activity. Together, these findings support the idea that rg plays an important role in the integration of different signals required for the exact regulation of cone cell development and survival.

Genetic Modifier Screens on Hairless Gain-of-Function Phenotypes Reveal Genes Involved in Cell Differentiation, Cell Growth and Apoptosis in Drosophila melanogaster

“…Several genes encoding signaling pathway components were identified. Apart from N, various components of the EGFR pathway were found, some of which had not yet come up in other screens [leonardo (leo), sprouty], highlighting a close link between N and EGFR signaling in the regulation of apoptosis (Miller and Cagan 1998;Wech and Nagel 2005). Isolation of several members of the JNK pathway in the loss-offunction screen supports our conclusion from the gainof-function screen that H might mediate cell death via …”

“…Apart from an increase in cell proliferation, this could be partly a consequence of impaired apoptosis, since the Notch signal is required for the survival of cone cells in the Drosophila pupal eye (Go et al 1998;Wech and Nagel 2005). Moreover, activation of Notch inhibits apoptosis mediated by presenilin, suggesting protection of neurons from apoptotic cell death by Notch signaling (Ye and Fortini 1999).…”

Drosophila rugoseIs a Functional Homolog of MammalianNeurobeachinand Affects Synaptic Architecture, Brain Morphology, and Associative Learning

“…A dominant-negative form of LRBA (lacking BEACH-WD40 domains) reduces the phosphorylation of EGFR and MAPK and sensitizes cancer cells to apoptosis (Wang et al, 2004). This interaction with growth factor receptor signaling, more specifically EGFR, MAPK, and Notch signaling, has been shown previously for Rugose in eye development (Schreiber et al, 2002;Shamloula et al, 2002;Wech and Nagel, 2005). In Caenorhabditis elegans, loss of the Rugose ortholog sel-2 also results in aberrant patterning of vulvar precursor cells in a Notchdependent manner (de Souza et al, 2007).…”

“…The typical organized structure of an ommatidium results from spatially restricted cell death depending on the balance between epidermal growth factor receptor (EGFR) and Notch signaling (Doroquez and Rebay, 2006). Rugose has been shown to interact genetically with components of the EGFR and Delta-Notch pathway (Schreiber et al, 2002;Shamloula et al, 2002;Wech and Nagel, 2005). In the past, human neurological disorders have been successfully modeled in Drosophila, providing valuable insights into disease mechanisms and protein functions (Bier, 2005;Bilen and Bonini, 2005).…”

“…In Drosophila, these proteins have a common ortholog, namely Rugose (Rg). Rg mutants display a rough eye phenotype primarily resulting from cone cell loss, defective ommatidial organization, absence of photoreceptors, and disorganized pigment cell lattice (Shamloula et al, 2002;Shamloula, 2003;Wech and Nagel, 2005). The typical organized structure of an ommatidium results from spatially restricted cell death depending on the balance between epidermal growth factor receptor (EGFR) and Notch signaling (Doroquez and Rebay, 2006).…”