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Investigating the function of the Receptor Tyrosine Kinase ALK during Drosophila melanogaster development
Umeå universitet, Teknisk-naturvetenskaplig fakultet, Umeå centrum för molekylär patogenes (UCMP).
2004 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The Drosophila melanogaster gene Anaplastic Lymphoma Kinase (DAlk) is homologous to mammalian Alk, which is a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). In humans the t(2;5) translocation involving the Alk locus encodes an active form of Alk that is the causative agent in Non-Hodgkin’s Lymphoma (Morris et al., 1994). Alk has also been associated with other cancers such as inflammatory myofibroblastic tumours (IMTs). The physiological function of the Alk RTK has not been described in any system until very recently, and is still not defined in vertebrates. The molecular similarity between Drosophila Alk and mammalian Alk suggested that mutation of Alk in flies may affect similar functional and developmental processes, and thus lead to some understanding of Alk function in vivo.

By employing an EMS mutagenesis screen we were able to obtain loss-of-function mutants in the Drosophila DAlk gene. Eleven independent DAlk mutants were identified and characterized. DAlk is normally expressed in the developing gut and in the CNS. DAlk mutant animals have a lethal phenotype and die at late embryonic stages or as 1st instar larva. In DAlk mutant embryos there is a complete failure in the development of the midgut whereas the CNS appears normal. The midgut consists of visceral musculature that is syncytial and is formed by fusion of multiple myoblasts. This is a dynamic process where two types of myoblasts, i.e. fusion-competent-myoblasts and founder-cells that function as seeds for muscle formation, fuse. In DAlk homozygous embryos there is no founder cell specification, which explains the failure of midgut formation in these embryos.

Recently a novel secreted molecule Jelly Belly (Jeb) was identified. Jeb is expressed in the tissue neighbouring the DAlk expressing cells of the developing visceral mesoderm. Jeb mutant embryos show a phenotype that is similar to that of DAlk mutant embryos. We have been able to show that Jeb is the ligand for DAlk in the developing visceral mesoderm and that Jeb binding stimulates a DAlk driven ERK signaling pathway. This leads to the expression of Dumbfounded (duf)/kin of Irregular chiasm-C (kirre), a founder-cell specific immunoglobulin that has an important role in myoblast aggregation and fusion.

The functional Drosophila midgut is made up of the visceral muscle that encircles the endodermal tube. This tube formation includes migration of cells originating in the anterior and posterior parts of the embryo, first along the anterior-posterior axis using the visceral mesoderm as a template, then dorsally and ventrally. In DAlk mutant embryos there is no visceral muscle fusion and both the visceral mesoderm and the endoderm fail to undergo dorsal-ventral migration.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten) , 2004. , s. 66
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 934
Nyckelord [en]
DAlk, receptor tyrosine kinase, Jeb, visceral muscle fusion, ERK, Drosophila, endoderm
Forskningsämne
molekylär cellbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-411ISBN: 91-7305-775-4 (tryckt)OAI: oai:DiVA.org:umu-411DiVA, id: diva2:143395
Disputation
2004-12-10, Hörsal E04, 6L, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Tillgänglig från: 2004-11-01 Skapad: 2004-11-01 Senast uppdaterad: 2009-05-08Bibliografiskt granskad
Delarbeten
1. Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo.
Öppna denna publikation i ny flik eller fönster >>Identification and characterization of DAlk: a novel Drosophila melanogaster RTK which drives ERK activation in vivo.
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2001 (Engelska)Ingår i: Genes to Cells, ISSN 1356-9597, E-ISSN 1365-2443, Vol. 6, nr 6, s. 531-544Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:umu:diva-4344 (URN)10.1046/j.1365-2443.2001.00440.x (DOI)
Tillgänglig från: 2004-11-01 Skapad: 2004-11-01 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
2. A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster
Öppna denna publikation i ny flik eller fönster >>A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster
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2003 (Engelska)Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 4, nr 8, s. 781-786Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The Drosophila melanogaster gene Anaplastic lymphoma kinase (Alk) is homologous to mammalian Alk, which encodes a member of the Alk/Ltk family of receptor tyrosine kinases (RTKs). In humans, the t(2;5) translocation, which involves the ALK locus, produces an active form of ALK, which is the causative agent in non-Hodgkin's lymphoma. The physiological function of the Alk RTK, however, is unknown. In this paper, we describe loss-of-function mutants in the Drosophila Alk gene that cause a complete failure of the development of the gut. We propose that the main function of Drosophila Alk during early embryogenesis is in visceral mesoderm development.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2003
Identifikatorer
urn:nbn:se:umu:diva-4345 (URN)10.1038/sj.embor.embor897 (DOI)
Tillgänglig från: 2004-11-01 Skapad: 2004-11-01 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
3. Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion
Öppna denna publikation i ny flik eller fönster >>Jeb signals through the Alk receptor tyrosine kinase to drive visceral muscle fusion
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2003 (Engelska)Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 425, nr 6957, s. 512-516Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:umu:diva-3564 (URN)14523447 (PubMedID)
Tillgänglig från: 2008-10-29 Skapad: 2008-10-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
4. Visceral muscle fusion is essential for the dorsal-ventral migration of the endoderm in Drosophila.
Öppna denna publikation i ny flik eller fönster >>Visceral muscle fusion is essential for the dorsal-ventral migration of the endoderm in Drosophila.
Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:umu:diva-4347 (URN)
Tillgänglig från: 2004-11-01 Skapad: 2004-11-01 Senast uppdaterad: 2010-01-13Bibliografiskt granskad

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