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Ethan Bier

University of California, San Diego

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Lawrence T. Reiter

University of Tennessee Health Science Center

Yuh Nung Jan

Howard Hughes Medical Institute

Lily Yeh Jan

Howard Hughes Medical Institute

Harald Vaessin

The Ohio State University

Annabel Guichard

University of California, San Diego

Georgianna G. Zimm

University of California, San Diego

Megan Bowers

University of Zurich

Jennifer Trimble-Morgan

University of California, San Diego

E. H. Grell

California State University, San Marcos

Mark A. Sturtevant

University of California, San Diego

Cooperative Institutions

University of California, San Diego

Howard Hughes Medical Institute

University of California, San Francisco

California State University, San Marcos

University of California, Berkeley

Baylor College of Medicine

University of Zurich

University of Pittsburgh

New York University

Université Libre de Bruxelles

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Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase

Human Molecular Genetics (2006)

Lawrence T. Reiter Tiffany N. Seagroves Megan Bowers Ethan Bier

We applied genetic tools available in Drosophila to identify candidate substrates of the UBE3A ubiquitin ligase, the gene responsible for Angelman syndrome (AS). Human UBE3A was expressed in Drosophila heads to identify proteins differentially regulated in UBE3A-expressing versus wild-type extracts. Using two-dimensional gel and MALDI-TOF analysis, we detected 20 proteins that were differentially regulated by over-expression of human UBE3A in Drosophila heads. One protein responsive to UBE3A was the Rho-GEF pebble (pbl). Here, we present three lines of evidence suggesting that UBE3A regulates Pbl. First, we show genetic evidence that UBE3A and the Drosophila de-ubiquitinase fat facets (faf) exert opposing effects on Pbl function. Secondly, we find that both Pbl and ECT2, the mammalian orthologue of Pbl called epithelial cell transforming sequence 2 oncogene, physically interact with their respective ubiquitin E3 ligases. Finally, we show that Ect2 expression is regulated by Ube3a in mouse neurons as the pattern of Ect2 expression is dramatically altered in the hippocampus and cerebellum of Ube3a null mice. These results suggest that an orthologous UBE3A post-translational regulatory pathway regulates neuronal outgrowth in the mammalian brain and that dysregulation of this pathway may result in neurological phenotypes including AS and possibly other autism spectrum disorders.

UBE3A

Angelman Syndrome

10.1093/hmg/ddl225

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Citations (101)

brother of rhomboid, a rhomboid-Related Gene Expressed during Early Drosophila Oogenesis, Promotes EGF-R/MAPK Signaling

Developmental Biology (2000)

Annabel Guichard Margaret Roark Matthew Ronshaugen Ethan Bier

Rhomboid

10.1006/dbio.2000.9851

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Citations (54)

Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila

Protein & Cell (2011)

Michael F. Wangler Lawrence T. Reiter Georgianna G. Zimm Jennifer Trimble-Morgan Jane Y. Wu

Peroxiredoxin

10.1007/s13238-011-1073-7

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Citations (3)

prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila

Harald Vaessin E. H. Grell Erica Wolff Ethan Bier Lily Yeh Jan

Neurite

Genetic screen

Enhancer trap

10.1016/0092-8674(91)90367-8

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Citations (360)

A screen for dominant mutations applied to components in the Drosophila EGF-R pathway

Proceedings of the National Academy of Sciences (2002)

Annabel Guichard Shaila Srinivasan Georgianna G. Zimm Ethan Bier

The Drosophila epidermal growth factor receptor (EGF-R) controls many critical cell fate choices throughout development. Several proteins collaborate to promote localized EGF-R activation, such as Star and Rhomboid (Rho), which act sequentially to ensure the maturation and processing of inactive membrane-bound EGF ligands. To gain insights into the mechanisms underlying Rho and Star function, we developed a mutagenesis scheme to isolate novel overexpression activity (NOVA) alleles. In the case of rho , we isolated a dominant neomorphic allele, which interferes with Notch signaling, as well as a dominant-negative allele, which produces RNA interference-like flip-back transcripts that reduce endogenous rho expression. We also obtained dominant-negative and neomorphic Star mutations, which have phenotypes similar to those of rho NOVA alleles, as well as dominant-negative Egf-r alleles. The isolation of dominant alleles in several different genes suggests that NOVA mutagenesis should be widely applicable and emerge as an effective tool for generating dominant mutations in genes of unknown function.

Rhomboid

10.1073/pnas.052028699

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Citations (20)

Homophila: human disease gene cognates in Drosophila

Nucleic Acids Research (2002)

Samson Chien Lawrence T. Reiter Ethan Bier Michael Gribskov

Although many human genes have been associated with genetic diseases, knowing which mutations result in disease phenotypes often does not explain the etiology of a specific disease. Drosophilamelanogaster provides a powerful system in which to use genetic and molecular approaches to investigate human genetic diseases. Homophila is an intergenomic resource linking the human and fly genomes in order to stimulate functional genomic investigations in Drosophila that address questions about genetic disease in humans. Homophila provides a comprehensive linkage between the disease genes compiled in Online Mendelian Inheritance in Man (OMIM) and the complete Drosophila genomic sequence. Homophila is a relational database that allows searching based on human disease descriptions, OMIM number, human or fly gene names, and sequence similarity, and can be accessed at http://homophila.sdsc.edu.

Mendelian inheritance

Human disease

10.1093/nar/30.1.149

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Citations (200)

Role of Helix-Loop-Helix Proteins in Drosophila Neurogenesis

Cold Spring Harbor Symposia on Quantitative Biology (1990)

Harald Vaessin Michael Caudy Ethan Bier Lily Yeh Jan Yuh Nung Jan

The development of the nervous system in invertebrate and vertebrate systems is initiated by the determination of a subset of neuroectodermal cells to become neuronal precursor cells. In this process, neuroectodermal cells choose between two principal developmental pathways and subsequently differentiate into either neuronal or epidermal precursors. In the early developmental processes of spatial subdivision and segmentation in Drosophila (and to some degree in vertebrate systems), DNA-binding proteins containing either the homeobox or zinc finger domain are instrumental. These classes of transcription factors have not been found to be regulators of the initial steps of neurogenesis. In contrast, several members of a recently defined class of DNA-binding proteins containing the so-called helix-loop-helix (HLH) domain play an important role in the choice between neurogenesis and epidermogenesis in Drosophila (Ghysen and Dambly-Chaudiere 1989; Knust and Campos-Ortega 1989). Other HLH-domain-containing proteins also appear to control cell fate, such as mesoderm formation (Thisse et...

Basic helix-loop-helix

Helix (gastropod)

10.1101/sqb.1990.055.01.026

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Citations (18)

Down-regulation of Drosophila Egf-r mRNA levels following hyperactivated receptor signaling

Development (1994)

Mark A. Sturtevant Jason O’Neill Ethan Bier

ABSTRACT Internalization of ligand-receptor complexes is a well-documented mechanism for limiting the duration and magnitude of a signaling event. In the case of the EGF-Receptor (EGF-R), exposure to EGF or TGF-α results in internalization of up to 95% of the surface receptor pool within 5 minutes of exposure to ligand. In this report, we show that levels of Drosophila Egf-r mRNA are strongly down-regulated in epidermal cells likely to have recently undergone high levels of EGF-R signaling. The cells in which Egf-r mRNA levels are down-regulated express the rhomboid gene, which is thought to locally amplify EGF-R signaling. Widespread Egf-r mRNA down-regulation can be induced by ubiquitous expression of rhomboid or by eliminating the Gap1 gene. These results suggest that cells engaged in intense EGF-R/RAS signaling limit the duration of the signal through a combination of short-acting negative feedback mechanisms such as receptor internalization followed by a longer lasting reduction in receptor transcript levels. Control of Egf-r mRNA levels by altering transcription or mRNA stability is a new tier of regulation to be considered in analysis of EGF-R signaling during development.

Internalization

10.1242/dev.120.9.2593

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Citations (46)

Using Drosophila melanogaster to uncover human disease gene function and potential drug target proteins

Expert Opinion on Therapeutic Targets (2002)

Ethan Bier Lawrence T. Reiter

AbstractThe fruit fly Drosophila melanogaster is a powerful genetic model organism, which has been instrumental in the determination of essential developmental and neurological pathways conserved from invertebrates to humans. With the completion of both the human and Drosophila genomes, the revelation that we are more similar to this simple organism than previously suspected was realised. 75% of human genetic disease genes have clear homologues in the fly. By utilising an array of genetic tools available to disrupt or misexpress these proteins, it is now feasible to perform large-scale genetic screens in Drosophila to identify other members of a particular human genetic pathway. This review outlines some of the reasons Drosophila is a useful tool for the discovery of therapeutic targets, covers some of the tools available to manipulate this organism and discusses specific examples of how to use Drosophila as a genetic test tube for revealing proteins which act in a common pathway.Keywordscross-genomicsdisease modelsDrosophilamodel organisms

Model Organism

Genetic screen

Human disease

10.1517/14728222.6.3.387

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Citations (40)

Drosophila, the golden bug, emerges as a tool for human genetics

Nature Reviews Genetics (2005)

Melanogaster

Human disease

Model Organism

10.1038/nrg1503

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Citations (593)