Gertrud M Schupbach
Princeton University
Project start date: 2007-02-01
Project end date: 2015-01-31
Sponsored Links Excellgen http://Excellgen.com
EGF RECEPTOR MEDIATED SIGNALING IN DROSPHILIA
Gertrud M Schupbach, Professor
Princeton University, Office Of Research And Project Administration, Princeton, Nj 08544-0036
Grant 5R01GM077620-04 from National Institute Of General Medical Sciences
Abstract: Cell-cell communication plays an important role in the development of many tissues. We are studying signaling processes between the female germline and its surrounding follicle cells in the ovary of Drosophila melanogaster. We have shown that the Drosophila homolog of the Epidermal Growth Factor Receptor (Egfr) is expressed in the follicle cells and receives a highly controlled signal from the germline encoded by the gene gurken. Restricted activation of the Egfr by Gurken (a TGF-alpha like protein) initiates several different follicle cell responses and is required for axis formation of the egg and embryo. Our goal is to study the regulation of signal production in the germline and the patterning and differentiation processes that are activated in the follicle cells in response to receptor activation. Our specific aims are 1) Analysis of a meiotic checkpoint mechanism that regulates Gurken translation. We have shown that DMA repair during meiosis is coupled via a meiotic checkpoint to translational control of Gurken in the oocyte cytoplasm. We will analyze genes that act in this pathway using both genetic and biochemical approaches. 2) Translational regulation of Gurken RNA. We will determine how the meiotic checkpoint regulates translation of Gurken as well as investigating other mechanisms of translational control that operate on Gurken. This will involve analysis of the gene Vasa as well as three new genes that we have found to affect Gurken protein levels. 3) Analysis of the response pathway acting in the follicle cells of the ovary. We have defined several specific patterning responses to Egfr activation in the follicle cells. In addition, the Egfr is also required for survival and normal cellular differentiation of the follicle cells. We will identify and analyze target genes acting downstream in these processes. This will involve the analysis of new mutations identified in mosaic follicle cell screens. Mutations in checkpoint genes, as well as unregulated activation of the human homologs of Egfr have been implicated in several forms of cancer, notably breast cancer. Our work will elucidate new roles of checkpoint genes, as well as analyzing the normal cellular pathways that regulate the activity of this receptor. It will also define downstream effector pathways operating in the follicle cell epithelium, which serves as a model system for epithelial development and differentiation
Keywords: Affect; Anterior; Aubergine; BRCA2; BRCA2 gene; Behavior; Biochemical; Biological Models; Body Tissues; Breast Cancer 2 Gene; Breast Cancer 2, Early Onset Gene; Breast Cancer Type 2 Susceptibility Gene; Brinjal; Cancer of Breast; Cancers; Candidate Disease Gene; Candidate Gene; Cell Communication; Cell Communication and Signaling; Cell Cycle; Cell Differentiation; Cell Differentiation process; Cell Division Cycle; Cell Interaction; Cell Nucleus; Cell Signaling; Cell-to-Cell Interaction; Cells; Coupled; Couples; Cytoplasm; DNA; DNA Damage Repair; DNA Repair; Deoxyribonucleic Acid; Development; Dorsal; Drosophila; Drosophila EGF receptor homolog; Drosophila Egfr protein; Drosophila genus; Drosophila melanogaster; EC 2.7; EGFR; ERBB Protein; ERBB1; Egfr protein, Drosophila; Egg Shell; Eggplant; Embryo; Embryonic; Enhancers; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Related Transforming Growth Factor; Epithelial; Epithelial Cells; Epithelium; Event; FANCB; FANCD1; Female; Fruit Fly, Drosophila; Gene Arrangement; Gene Order; Gene Position; Gene Products, RNA; Gene Targeting; GeneHomolog; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genetic screening method; Genital System, Female, Ovary; Goals; HER1; Hereditary Breast Cancer 2; Homolog; Homologous Gene; Homologue; Human; Human, General; Intracellular Communication and Signaling; Investigators; Kinases; Ligands; Link; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Malignant neoplasm of breast; Man (Taxonomy); Man, Modern; Mediating; Meiosis; Micro RNA; MicroRNAs; Model System; Models, Biologic; Modification; Molecular; Morphology; Mutation; Nature; Nucleus; Oocytes; Oogenesis; Ovarian Follicle; Ovary; Ovocytes; PTK Receptors; Pathway interactions; Pattern; Phosphotransferases; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Process; Production; Programs (PT); Programs [Publication Type]; Proteins; Quelling; R01 Mechanism; R01 Program; RNA; RNA Interference; RNA Silencing; RNA Silencings; RNA, Non-Polyadenylated; RNAi; RPG; RTK; Receptor Activation; Receptor Protein; Receptor Protein-Tyrosine Kinases; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Regulation; Repression; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Ribonucleic Acid; Role; Sequence-Specific Posttranscriptional Gene Silencing; Signal Transduction; Signal Transduction Systems; Signaling; Squash (Food); Squashes; System; System, LOINC Axis 4; TGF A; TGF-alpha; TGFA; TGFalpha; Targetings, Gene; Testing; Tissues; Transforming Growth Factor alpha; Transforming Growth Factor alpha Receptor; Translational Regulation; Translations; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Unscheduled DNA Synthesis; Work; biological signal transduction; brca 2 gene; c-erbB-1; c-erbB-1 Protein; computerized data processing; data processing; egg; epidermal growth factor receptor homolog, Drosophila; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; experiment; experimental research; experimental study; fruit fly; gene product; genetic testing; genome mutation; insight; malignancy; malignant breast neoplasm; mei-41; meiotic; miRNA; neoplasm/cancer; novel; pathway; programs; protein distribution; proto-oncogene protein c-erbB-1; receptor; receptor-mediated signaling; repair; repaired; research study; response; signal processing; social role; torpedo protein, Drosophila; translation factor
Project start date: 2007-02-01
Project end date: 2011-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
5R01GM077620-04 (2010): $289721
Grants awarded to Gertrud M Schupbach
SPATIAL PATTERN OF THE EGG CHAMBER IN DROSOPHILA
Gertrud M Schupbach, Professor
Molecular Biologyprinceton University
office Of Research And Project Administration
princeton, Nj 085440036
Grant 5R01GM040558-07 from National Institute Of General Medical Sciences IRG: GEN
Abstract: The aim of this project is the analysis how spatial asymmetries arise in the developing egg chamber of Drosophila melanogaster. We have shown that a signalling process between the germline and the overlying follicle cells establishes the dorso-ventral pattern of both the egg shell and the embryo. We found that torpedo, a central gene in this cell communication pathway, encodes the Drosophila homolog of the vertebrate Epidermal Growth Factor receptor (EGFr). We will analyze at the molecular level a set of 32 torpedo alleles which differentially affect receptor function in different cell types. To analyze the upstream germline processes involved in torpedo activation we propose a detailed genetic and molecular analysis of the gene cornichon which is presently our best candidate for encoding a ligand of the receptor. We will subsequently analyze the interactions between cornichon and gurken, fs(1)K10, capuccino, and spire, genes that also act in the germline and are involved in ligand production. This will allow us to describe the pathway of temporal and spatial control used by the system for ligand production. We will analyze the two cellular response pathways that are activated by the torpedo receptor the establishment of dorsal follicle cell fates and the regulation of a new, ventralizing signal which is produced in the follicle cells and transmitted back to the embryo. We have identified a candidate class of genes for the first response pathway. We propose to analyze this class and identify genes that promote the establishment of dorsal follicle cell fates. We have also identified a gene (windbeutel) that acts in the second pathway and participates in the production of a new signal in the follicle cells which ultimately established embryonic cell fates. Genetic and molecular techniques will be used to analyze windbeutel. In addition, a search for additional genes that act in the torpedo pathway will be performed by screening for enhancer or suppressor mutations. We will also analyze mutations that affect early events in egg chamber patterning. This will provide information about the primary mechanisms that are used in Drosophila to establish the initial anterior-posterior and dorso-ventral asymmetries. The proposed research will allow us to determine how a spatially and temporally controlled activation of the torpedo receptor tyrosine kinase is achieved in development, and provide a detailed understanding of the different developmental pathways that are controlled by receptor activation. Excellent biochemical data on the mode of action of such receptors has been obtained using vertebrate tissue culture systems. Our studies in the egg chamber of Drosophila will complement such analyses, and yield insights into the role of such receptors in the developing organism
Project start date: 1988-09-01
Project end date: 1996-08-31
5R01GM040558-07 (1994): $247238
5R01GM040558-06 (1993): $264911
EGF RECEPTOR MEDIATED SIGNALING IN DROSOPHILA
Gertrud M Schupbach, Professor
Princeton University Office Of Research And Project Administration Princeton, Nj 085440036
Grant 5P01CA041086-200006 from National Cancer Institute
Abstract: Receptor tyrosine kinases (RTK) are key molecules controlling cell growth and differentiation, and mutations in major RTKs and their targets have been implicated in certain forms of cancer. We investigate the mechanisms involved in the activation of the Drosophila homolog of the Epidermal Growth Factor receptor (Egfr) during oogenesis, and the cellular responses pathways activated in the follicle cells. We focus on our recent finding that activation of the receptor in oogenesis is regulated by the meiotic cell cycle via a checkpoint kinase. We also investigate how activity of Egfr regulates major developmental events in the follicle cells, resulting in the patterning of egg shell and embryo. Three major goals (1) Analysis of the meiotic checkpoint mechanism that regulates Gurken (Grk) production. We will perform genetic tests of candidate mutations, screen for new mutations that may act in conjunction with the checkpoint kinase Kei-41, and determine whether they act in conjunction with the checkpoint kinase Mei-41 and determine whether they act in the process that couples the DNA repair sensing mechanism in meiosis to events in the oocyte cytoplasm. (2) Translational regulation of grk RNA. We will determine how the meiotic checkpoint regulates translation of grk. We will also investigate checkpoint independent, parallel pathways of translational regulation of grk. We have found a gene, encore, which affects Grk protein accumulation. Encore and other candidates will be tested for genetic physical interactions with the known translational regulators of grk RNA. (3) Analysis of the response pathways acting in the follicle cells of the ovary. We will focus on the three cellular responses that depend on Egfr activation in the follicle cells. We will identify and analyze new target genes acting downstream in these processes using either microarray techniques, or a mosaic follicle cell system. We will continue with the analysis of the Drosophila homolog of the Cb1 oncogene. In collaboration with Wieschaus we will analyze interactions of Egfr with the Armadillo/beta catenin pathway in follicle cells.
Keywords: Drosophilidae, arthropod genetics, biological signal transduction, cell growth regulation, epidermal growth factor, growth factor receptor, oogenesis, receptor expression, RNA, cell differentiation, egg /ovum, gene expression, gene mutation, genetic translation, meiosis, ovary, protein tyrosine kinase, genetic screening, microarray technology
Sponsored Links Excellgen http://Excellgen.com
EGF Receptor Mediated Signaling In Drosphilia
Gertrud M Schupbach, Professor
Princeton University Office Of Research And Project Administration Princeton, Nj 085440036
Grant 1R01GM077620-01A1 from National Institute Of General Medical Sciences IRG: DEV1
Abstract: Cell-cell communication plays an important role in the development of many tissues. We are studying signaling processes between the female germline and its surrounding follicle cells in the ovary of Drosophila melanogaster. We have shown that the Drosophila homolog of the Epidermal Growth Factor Receptor (Egfr) is expressed in the follicle cells and receives a highly controlled signal from the germline encoded by the gene gurken. Restricted activation of the Egfr by Gurken (a TGF-alpha like protein) initiates several different follicle cell responses and is required for axis formation of the egg and embryo. Our goal is to study the regulation of signal production in the germline and the patterning and differentiation processes that are activated in the follicle cells in response to receptor activation. Our specific aims are 1) Analysis of a meiotic checkpoint mechanism that regulates Gurken translation. We have shown that DMA repair during meiosis is coupled via a meiotic checkpoint to translational control of Gurken in the oocyte cytoplasm. We will analyze genes that act in this pathway using both genetic and biochemical approaches. 2) Translational regulation of Gurken RNA. We will determine how the meiotic checkpoint regulates translation of Gurken as well as investigating other mechanisms of translational control that operate on Gurken. This will involve analysis of the gene Vasa as well as three new genes that we have found to affect Gurken protein levels. 3) Analysis of the response pathway acting in the follicle cells of the ovary. We have defined several specific patterning responses to Egfr activation in the follicle cells. In addition, the Egfr is also required for survival and normal cellular differentiation of the follicle cells. We will identify and analyze target genes acting downstream in these processes. This will involve the analysis of new mutations identified in mosaic follicle cell screens. Mutations in checkpoint genes, as well as unregulated activation of the human homologs of Egfr have been implicated in several forms of cancer, notably breast cancer. Our work will elucidate new roles of checkpoint genes, as well as analyzing the normal cellular pathways that regulate the activity of this receptor. It will also define downstream effector pathways operating in the follicle cell epithelium, which serves as a model system for epithelial development and differentiation.
Keywords: cell, receptor, DNA, DNA repair, Drosophilidae, RNA, behavior, breast neoplasm, cell cycle, cell differentiation, communication, cytoplasm, egg /ovum, egg shell, emotion, epidermal growth factor, epithelium, female, gene, gene mutation, gene targeting, genetics, growth factor receptor, human, insight, lead, ligand, meiosis, microRNA, miotic, model, molecular genetics, morphology, oogenesis, ovary, play, protein, receptor expression, repression, role, tissue, translation factor, tyrosine
Project start date: 2007-02-01
Project end date: 2011-01-31
1R01GM077620-01A1 (2007): $292647
Spatial Patterning During Development
Gertrud M Schupbach, Professor
Princeton University
office Of Research And Project Administration
princeton, Nj 085440036
Grant 5P50GM071508-040001 from National Institute Of General Medical Sciences IRG: ZGM1
Keywords: biological signal transduction, cell differentiation, cell population study, computational biology, developmental genetics, embryogenesis, gene expression, genetic regulation arthropod genetics, cell cell interaction, cell cycle, cyclic AMP, epidermal growth factor, growth factor receptor, intermolecular interaction, oogenesis, protein localization, protein structure function, protozoal genetics, transcription factor Dictyostelium, Drosophilidae, embryo /fetus, microarray technology