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Characterization of the role of Vrp1 in cell fusion during the development of visceral muscle of Drosophila melanogaster
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2010 (English)In: BMC Developmental Biology, ISSN 1471-213X, E-ISSN 1471-213X, Vol. 10, no 86Article in journal (Refereed) Published
Abstract [en]

Background: In Drosophila muscle cell fusion takes place both during the formation of the somatic mesodermand the visceral mesoderm, giving rise to the skeletal muscles and the gut musculature respectively. The coreprocess of myoblast fusion is believed to be similar for both organs. The actin cytoskeleton regulator Verprolin actsby binding to WASP, which in turn binds to the Arp2/3 complex and thus activates actin polymerization. WhileVerprolin has been shown to be important for somatic muscle cell fusion, the function of this protein in visceralmuscle fusion has not been determined.Results: Verprolin is specifically expressed in the fusion competent myoblasts of the visceral mesoderm, suggestinga role in visceral mesoderm fusion. We here describe a novel Verprolin mutant allele which displays subtle visceralmesoderm fusion defects in the form of mislocalization of the immunoglobulin superfamily molecule Duf/Kirre,which is required on the myoblast cell surface to facilitate attachment between cells that are about to fuse,indicating a function for Verprolin in visceral mesoderm fusion. We further show that Verprolin mutant cells arecapable of both migrating and fusing and that the WASP-binding domain of Verprolin is required for rescue of theVerprolin mutant phenotype.Conclusions: Verprolin is expressed in the visceral mesoderm and plays a role in visceral muscle fusion as shownby mislocalization of Duf/Kirre in the Verprolin mutant, however it is not absolutely required for myoblast fusion ineither the visceral or the somatic mesoderm.

Place, publisher, year, edition, pages
BioMed Central, 2010. Vol. 10, no 86
Keyword [en]
Vrp1, fusion, visceral mesoderm, Duf
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-36983DOI: 10.1186/1471-213X-10-86OAI: oai:DiVA.org:umu-36983DiVA: diva2:356963
Projects
Exploiting Drosophila as a model system for studying Anaplastic Lymphoma Kinase in vivo
Available from: 2010-10-14 Created: 2010-10-14 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Exploiting Drosophila as a model system for studying anaplastic lymphoma kinase in vivo
Open this publication in new window or tab >>Exploiting Drosophila as a model system for studying anaplastic lymphoma kinase in vivo
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anaplastic Lymphoma Kinase (ALK) is a Receptor Tyrosine Kinase (RTK) and an oncogene associated with several human diseases, but its normal function in humans and other vertebrates is unclear. Drosophila melanogaster has an ALK homolog, demonstrating that the RTK has been conserved throughout evolution. This makes Drosophila a suitable model organism for studying not only Drosophila ALK function, but also to study mammalian forms of ALK. In Drosophila the ligand Jeb activates ALK, initiating signaling crucial for visceral mesoderm development. The activating ligand for mammalian ALK is unclear, and for this reason Drosophila was employed in a cross-species approach to investigate whether Drosophila Jeb can activate mouse ALK. Jeb is unable to activate mouse ALK, and therefore mouse ALK is unable to substitute for and rescue the Drosophila ALK mutant phenotype. This suggests that there has been significant evolution in the ALK-ligand relationship between the mouse and Drosophila.

In humans ALK has recently been shown to be involved in the development of neuroblastoma, a cancer tumor in children. I have developed a Drosophila model for examining human gain of function ALK mutants found in neuroblastoma patients. The various ALK variants have acquired point mutations in the kinase domain that have been predicted to activate the RTK in a constitutive and ligand independent manner. When expressed in the fly eye, active human ALK mutants result in a rough eye phenotype, while inactive wild type ALK does not, due to the lack of an activating ligand in the fly. In this way  several of the ALK mutations identified in neuroblastoma patients could be confirmed to be activated in a ligand independent manner. Moreover, a novel ALK mutant; ALKF1174S, was discovered in a neuroblastoma patient and was in the Drosophila model shown to be a gain of function mutation, and a previously predicted gain of function mutation; ALKI1250T, was shown to be a kinase dead mutation. This fly model can also be used for testing ALK selective inhibitors, for identifying activating ligands for human ALK and for identifying conserved components of the ALK signaling pathway.

Gut musculature development in Drosophila is dependent on ALK signaling, while somatic muscle development is not. Proteins of the Wasp-Scar signaling network regulate Arp2/3-complex mediated actin polymerization, and I have investigated their function in visceral and somatic muscle fusion. I found that Verprolin and other members of this protein family are essential for somatic but not visceral muscle development. Despite fusion defects in both tissues in Verprolin and other examined mutants, gut development proceeds, suggesting that fusion is not crucial for visceral mesoderm development. Hence the actin polymerization machinery functions in both somatic and visceral muscle fusion, but this process only appears to be essential in somatic muscle development.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2010. 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1376
Keyword
Anaplastic lymphoma kinase, Receptor tyrosine kinase, Jeb, neuroblastoma, actin polymerization, Wasp, Scar, Vrp1, Arp2/3
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-36991 (URN)978-91-7459-090-6 (ISBN)
Public defence
2010-11-05, Major Groove, Byggnad 6L, Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Projects
Exploiting Drosophila as a model system for studying Anaplastic Lymphoma Kinase in vivo
Available from: 2010-10-15 Created: 2010-10-14 Last updated: 2010-10-15Bibliographically approved

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