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Identification of downstream targets of Alk signaling in Drosophila melanogaster
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Drosophila gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian ALK, a member of the Alk/Ltk family of receptor tyrosine kinases. In Drosophila Alk is crucial for development of the embryonic visceral mesoderm, where it is the receptor for Jelly Belly (Jeb) ligand. Jeb binding stimulates an Alk-driven, extracellular signal-regulated, kinase-mediated signaling pathway, which results in the expression of the downstream gene duf/kirre. The visceral mesoderm is made up from two different cell types, founder cells and fusion competent myoblasts. The Jeb-Alk signal transduction pathway drives specification of the founder cells of the Drosophila visceral muscle. In this work we aimed to identify genes specifically expressed in the founder cells and/or fusion competent myoblasts. Four genes from a number of candidiates were investigated further. These genes are Hand, expressed in founder cells, goliath, parcas and delilah, which are expressed in fusion competent myoblasts. Hand is a basic helix-loop-helix (bHLH) transcription factor. Alk-mediated signal transduction drives the expression of the bHLH transcription factor hand in vivo, and loss of Alk function results in a complete lack of hand expression in the visceral mesoderm, while Alk gain of function results in an expansion of hand expression. There are no obvious defects in the visceral muscle fusion process hand mutant animals, suggesting that Hand is not critical for visceral muscle fusion per se.

I have studied another molecule Goliath, a putative RING finger E3 ligase. goliath is specifically expressed in the FCM of visceral and somatic muscles. goliath mutant animals do not display any obvious muscle phenotypes, perhaps reflecting a redundant role with CG10277, which encodes a second Goliath family protein in Drosophila. Deletion mutation of the CG10277 locus does not result in muscle defects either, and generation of double mutants of goliath and CG10277 will be required to determine their function in vivo.

In addition, I have studied another bHLH transcription factor Delilah and its role in muscle development. We show that delilah is expressed in visceral muscle, somatic muscles and in tendon cells. Delilah mutant animals display a held out wing phenotype and are unable to fly. Inducible RNAi against delilah results in a similar phenotype. Delilah is transcriptionally regulated by mef2 and biniou, early regulators of muscle development. While delilah appears to function in tendon cells, we were unable to find any obvious phenotype in either visceral or somatic muscles. In order to further investigate the underlying mechanism of Delilah function we have used Tandem affinity purification (TAP) methodology followed by mass spectrometry to identify Delilah binding partners. This analysis suggests a number of candidate functional partners for the Delilah protein.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten) , 2008. , 65 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1223
Keyword [en]
Drosophila, Alk, Jeb, visceral muscles, somatic muscles, Delilah, Goliath, Hand
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1894ISBN: 978-91-7264-668-1 (print)OAI: oai:DiVA.org:umu-1894DiVA: diva2:142334
Public defence
2008-11-17, Betula, Bldg 6M, Umea University, Umea, 09:00 (English)
Opponent
Supervisors
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion
Open this publication in new window or tab >>Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion
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2003 (English)In: Nature, ISSN 0028-0836, Vol. 425, no 6957, 512-516 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3564 (URN)14523447 (PubMedID)
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2009-05-08Bibliographically approved
2. The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut.
Open this publication in new window or tab >>The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut.
2006 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, Vol. 351, no 4, 839-846 p.Article in journal (Refereed) Published
Abstract [en]

During embryonic development the midgut visceral muscle is formed by fusion of cells within the visceral mesoderm, a process initiated by the specification of a specialised cell type, the founder cell, within this tissue. Activation of the receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) in the developing visceral muscle of Drosophila melanogaster initiates a signal transduction pathway required for muscle fusion. In this paper, we have investigated downstream components which are regulated by this novel signalling pathway. Here we show that Alk-mediated signal transduction drives the expression of the bHLH transcription factor Hand in vivo. Loss of Alk function results in a complete lack of Hand expression in this tissue, whereas Alk gain of function results in an expansion of Hand expression. Finally, we have investigated the process of muscle fusion in the gut of Hand mutant animals and can find no obvious defects in this process, suggesting that Hand is not critical for visceral muscle fusion per se.

Keyword
Animals, Basic Helix-Loop-Helix Transcription Factors/analysis/genetics/*metabolism, Drosophila Proteins/analysis/genetics/*metabolism, Drosophila melanogaster/anatomy & histology/*embryology, Embryo; Nonmammalian/chemistry/metabolism, Intestines/chemistry/*embryology/metabolism, Mesoderm/chemistry/metabolism, Muscle; Smooth/chemistry/*embryology/metabolism, Mutation, Protein-Tyrosine Kinases/genetics/*physiology, Signal Transduction, Transcription Factors/analysis/metabolism
Identifiers
urn:nbn:se:umu:diva-17924 (URN)10.1016/j.bbrc.2006.10.117 (DOI)17094947 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved
3. Mutation of the Drosophila bHLH transcription factor Delilah results in a held out wing phenotype suggesting a role in myotendonous junction formation
Open this publication in new window or tab >>Mutation of the Drosophila bHLH transcription factor Delilah results in a held out wing phenotype suggesting a role in myotendonous junction formation
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3566 (URN)
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2010-01-13Bibliographically approved
4. Analysis of the bHLH transcription factor Delilah protein interactome in Drosophila with tandem affinity purification-mass spectrometry
Open this publication in new window or tab >>Analysis of the bHLH transcription factor Delilah protein interactome in Drosophila with tandem affinity purification-mass spectrometry
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3567 (URN)
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2010-01-13Bibliographically approved
5. Mutational analysis of the fusion competent myoblast specific E3- ligase Goliath in Drosophila melanogaster
Open this publication in new window or tab >>Mutational analysis of the fusion competent myoblast specific E3- ligase Goliath in Drosophila melanogaster
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3568 (URN)
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2010-01-13Bibliographically approved

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