Characterization of the Drosophila growth-regulatory genes gang of four, archipelago, and erupted Pubblico

Abstract

The reproducible size and shape of an organism relies on a balance of genetically controlled signaling pathways that regulate tissue growth. While patterned activation of these pathways shapes developing tissues, deregulation of these same mechanisms can contribute to hyperplastic diseases like cancer. Because pathways regulating cell size and cell number are highly conserved, we chose to study the basic processes of growth control in the fruit fly, Drosophila melanogaster.

This dissertation presents work on three Drosophia growth-regulatory genes- gang of four, archipelago, and erupted. Though each gene was identified in a forward genetic screen for mutations causing tissue overgrowth, each has unique properties. These findings show that gang of four behaves genetically as gain-of-function for an RNA binding protein, bru-3, and affects growth and patterning via multiple signaling pathways. Likewise, mutations in human archipelago are associated with T-cell acute lymphoblastic leukemia, and elevated Notch signaling causes phenotypes in archipelago mutant tissue in the fly reminiscent of those in the mouse T-cell lineage, thus uncovering a conserved system in which to directly address clinically relevant aspects of archipelago biology. Finally, we show that erupted mutations deregulate signaling through the JAK-STAT pathway. The human ortholog of erupted, Tsg101, is involved in human cancers, but its roles in cellular transformation are unclear; therefore, further elucidation of erupted molecular mechanisms can also directly impact human disease. Collectively, I have identified conserved aspects of three recently isolated growth regulators, significantly advancing our fundamental understanding of growth control in a multicellular organism.

Table of Contents

Chapter I: Introduction

I.A. Purpose

I.B. Coordination of growth and patterning in development

I.C. The Model: Drosophila eye development

I.D. The Screen: Identification of novel growth-regulatory genes

I.E. gang of four

I.E1. bru-3

I.E2. MAPK Pathways

I.F. archipelago

I.F1. The Notch Signaling Pathway

I.G. erupted

I.G1. The JAK-STAT Pathway

I.H. REFERENCES

Chapter II: The gang of four gene regulates growth and patterning of the developing Drosophila eye

II.A. ABSTRACT

II.B. INTRODUCTION

II.C. RESULTS

II.C1. Isolation of the gang of four complementation group

II.C2. Mapping of the gfr locus

II.C3. gfr alleles regulate growth in the developing eye

II.C4. gfr alleles affect patterining of the developing eye

II.C5. gfr mutations confer a proliferative advantage and synergize with a block in cell death

II.C6. gfr alleles have Notch gain-of function phenotypes

II.C7. gfr interactions with the puc phosphatase

II.C8. gfr alleles decrease Cic levelsII.C9. gfr alleles are gain-of-function for bru-3

II.C10. bru-3 regulates Cic and eye size

II.D. DISCUSSION

II.E. MATERIALS AND METHODS

II.F. REFERENCES

Chapter III: The role of Notch activity in ago tumorigenesis

III.A. ABSTRACT

III.B. INTRODUCTION

III.C. RESULTS

III.C1. ago antagonizes Notch in vivo

III.C2. ago loss does not stabilize Notch protein in vivo

III.C3. Notch influences differentiation and growth downstream of ago

III.C4. ago limits p53-mediated apoptosis in the pupal eye

III.D. DISCUSSION

III.E. MATERIALS AND METHODS

III.F. REFERENCES

Chapter IV: The Drosophila tumor suppressor gene ept/tsg101 hyper-activates the JAK-STAT pathway
IV.A. ABSTRACT
IV.B. INTRODUCTION
IV.C. RESULTS
IV.C1. Activation of JAK-STAT signaling in ept mutant cells
IV.C2. Cell-autonomous effect of ept loss on Dome
IV.D. DISCUSSION
IV.E. MATERIALS AND METHODS
IV.F. REFERENCES
Chapter V: Future Directions and Concluding Remarks
V.A. FUTURE DIRECTIONS: gang of four
V.A1. Mapping
V.A2. gfr molecular mechanism
V.B. FUTURE DIRECTIONS: archipelago
V.B1. Is fly Notch an Ago substrate in vivo?
V.B2. What is the role of Notch in ago growth and differentiation defects?
V.C. FUTURE DIRECTIONS: erupted
V.D. CONCLUDING REMARKS
V.E. REFERENCES

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
Parola chiave	Drosophila tissue growth
Committee Chair / Thesis Advisor	Moberg, Kenneth H, Emory University
Committee Members	Chen, Ping, Emory University Neish, Andrew S, Emory University Yedvobnick, Barry, Emory University Fritz, Andreas, Emory University

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