Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation (original) (raw)
Related papers
Developmental control by the Drosophila EGF receptor homolog DER
Trends in Genetics, 1991
The DER protein has the canonical structure of a receptor tyrosine kinase belonging to the subclass that includes the vertebrate EGF receptor 1,2. While three members of this class have been identified in vertebrates, in Drosophila DER appears to be unique. The protein has a single transmembrane domain separating the intracellular and extracellular domains. The highest degree of sequence conservation is found in the intracellular kinase domain. The DER protein has also been shown to have tyrosine kinase activity, and can phosphorylate itself3. The carboxy-terminal region, beyond the kinase domain, contains the sites for autophosphorylation and shows the lowest degree of structural conservation, although this region plays a pivotal role in signal transduction (see below). The extracellular portion comprises four subdomains. Two are cysteinerich and are likely to generate the scaffold of the ligand-binding domain, but not its recognition specificity. The cysteine-rich subdomain closer to the membrane is the longer of the two. Interestingly, this structural feature is also found in the Caenorhabditis elegans EGF receptor homolog, encoded by the let-23 gene ~, but not in the vertebrate counterparts, indicating that the ancestral form of these receptors was probably similar to DER.
2009
Members of the Eyes absent (Eya) protein family play important roles in tissue specification and patterning by serving as both transcriptional activators and protein tyrosine phosphatases. These activities are often carried out in the context of complexes containing members of the Six and/or Dach families of DNA binding proteins. eyes absent, the founding member of the Eya family is expressed dynamically within several embryonic, larval and adult tissues of the fruit fly, Drosophila melanogaster. Loss-of-function mutations are known to result in disruptions of the embryonic head and central nervous system as well as the adult brain and visual system including the compound eyes. In an effort to understand how eya is regulated during development we have carried out a genetic screen that is designed to identify genes that lie upstream of eya and govern its expression. We have identified a large number of putative regulators including members of several signaling pathways. Of particular interest is the identification of both yan/anterior open and pointed, two members of the EGF Receptor signaling cascade. The EGFR pathway is known to regulate the activity of Eya through phosphorylation via MAPK. Our findings suggest that this pathway is also used to influence eya transcriptional levels. Together these mechanisms provide a route for greater precision in regulating a factor that is critical for the formation of a wide range of diverse tissues.
Developmental Biology, 1999
Dominant Ellipse mutant alleles of the Drosophila EGF receptor homologue (DER) dramatically suppress ommatidium development in the eye and induce ectopic vein development in the wing. Their phenotype suggests a possible role for DER in specifying the founder R8 photoreceptor cells for each ommatidium. Here we analyze the basis of Ellipse mutations and use them to probe the role of DER in eye development. We show that Elp mutations result from a single amino acid substitution in the kinase domain which activates tyrosine kinase activity and MAP kinase activation in tissue culture cells. Transformant studies confirmed that the mutation is hypermorphic in vivo, but the DER function was elevated less than by ectopic expression of the ligand spitz. Ectopic spi promoted photoreceptor differentiation, even in the absence of R8 cells. Pathways downstream of DER activation were assessed to explore the basis of these distinct outcomes. Elp mutations caused overexpression of the Notch target gene E(spl) m␦ and required function of Notch to suppress ommatidium formation. The Elp phenotype also depended on the secreted protein argos and was reverted in Elp aos double mutants. Complete loss of DER function in clones of null mutant cells led to delay in R8 specification and subsequently to loss of mutant cells. The DER null phenotype was distinct from that of either spitz or vein mutants, suggesting that a combination of these or other ligands was required for aspects of DER function. In normal development DER protein was expressed in most retinal cells, but at distinct levels. We used an antibody specific for diphospho-ERK as well as expression of the DER target gene argos to assess the pattern of DER activity, finding highest activity in the intermediate groups of cells in the morphogenetic furrow. However, studies of mutant genotypes suggested that this activity may not be required for normal ommatidium development. Since we saw distinct phenotypic effects of four different levels of DER activity associated with wild-type, null mutant, Elp mutant, or fully activated DER function, we propose that multiple thresholds separate several aspects of DER function. These include activation of N signaling to repress R8 specification, turning on argos expression, and recruiting photoreceptors R1-R7. It is possible that during normal eye development these thresholds are attained by different cells, contributing to the pattern of retinal differentiation.
A thousand and one roles for the Drosophila EGF receptor
Trends in Genetics, 1997
The wide range of roles played by the EGF receptor during Drosophila de Jelopment was first realized when, within one year, the embryonic lethal faint little ball mutation t-3, the female sterile torpedo mutation3 and the eye mutation Ellipse (Ref. 4) were all located at the EGF receptor locus, Egfr. The pleiotropic and inter-4 fit t c,~.~z © ;,~'~ ~L~,vi~.r .,~.n ~r ~d. All nr~L, r,~.,-a, ot¢~9~25,~7, $1,.oo • 7 t Genetwork is a regular column of news and information about lntemet resources for researchem in genetics and developmem (pp. 206-207). C, enetwork is compiled and edited with the help
Genetics, 2009
Members of the Eyes absent (Eya) protein family play important roles in tissue specification and patterning by serving as both transcriptional activators and protein tyrosine phosphatases. These activities are often carried out in the context of complexes containing members of the Six and/or Dach families of DNA binding proteins. eyes absent, the founding member of the Eya family is expressed dynamically within several embryonic, larval, and adult tissues of the fruit fly, Drosophila melanogaster. Loss-of-function mutations are known to result in disruptions of the embryonic head and central nervous system as well as the adult brain and visual system, including the compound eyes. In an effort to understand how eya is regulated during development, we have carried out a genetic screen designed to identify genes that lie upstream of eya and govern its expression. We have identified a large number of putative regulators, including members of several signaling pathways. Of particular int...
Cell, 1989
Recessive lethal mutations in the genetic locus of the Drosophila EGF receptor homolog (DER) were isolated. Identification of mutations in the gene is based on assays of DER protein autophosphorylation activity. Most DER alleles show little or no in vivo autophosphorylation. The ability to monitor these activities in vivo and in vitro offers a preliminary insight into the functional defects in the different mutant proteins. The identification of the DER locus was also confirmed by partial rescue of the mutant phenotype with a DER P-element construct. Homozygous DER mutants display a complex embryonic phenotype. Most notably, the anterior structures deteriorate, ventral denticle bands are missing, the germ band does not retract, and the central nervous system shows a collapse of commissure and midline pattern. Mutations in DER were shown to be allelic to the previously described locus faint little ball.
Development, 2003
Epidermal Growth Factor-receptor (Egfr) signaling is evolutionarily conserved and controls a variety of different cellular processes. In Drosophila these include proliferation, patterning, cell-fate determination, migration and survival. Here we provide evidence for a new role of Egfr signaling in controlling ommatidial rotation during planar cell polarity (PCP) establishment in the Drosophila eye. Although the signaling pathways involved in PCP establishment and photoreceptor cell-type specification are beginning to be unraveled, very little is known about the associated 90°rotation process. One of the few rotation-specific mutations known is roulette (rlt) in which ommatidia rotate to a random degree, often more than 90°. Here we show that rlt is a rotation-specific allele of the inhibitory Egfr ligand Argos and that modulation of Egfr activity shows defects in ommatidial rotation. Our data indicate that, beside the Raf/MAPK cascade, the Ras effector Canoe/AF6 acts downstream of Egfr/Ras and provides a link from Egfr to cytoskeletal elements in this developmentally regulated cell motility process. We provide further evidence for an involvement of cadherins and nonmuscle myosin II as downstream components controlling rotation. In particular, the involvement of the cadherin Flamingo, a PCP gene, downstream of Egfr signaling provides the first link between PCP establishment and the Egfr pathway.