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Investigating the function of Anaplastic Lymphoma Kinase
Umeå University, Faculty of Medicine, Medical Biosciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anaplastic Lymphoma Kinase (ALK) was discovered in 1994, as a chromosomal translocation, t(2;5)(p23;q35), often seen in Anaplastic Large Cell Lymphomas (ALCL). Since then ALK has been extensively studied in this disease as well as in different model organisms. Due to its expression pattern within the central and peripheral nervous system ALK has been implicated in neuronal development. This hypothesis has been further strengthened by studies from Drosophila which have shown Alk to have an important role in optic lobe development. A recently described ALK mouse knockout model do not indicate an essential role for ALK in development, although a potential role within the central nervous system was strengthened. This since ALK-/- animals has an increased number of progenitor cells in the hippocampus and display altered behavior.

The overall aim of the studies included in this thesis was to elucidate the function of ALK in the mouse. As a first step toward this goal we conducted an analysis of ALK mRNA and protein expression patterns during development. The strong expression of ALK in neuronal structures supports a role for ALK in neuronal development during embryogenesis.

To further investigate the function of ALK in a physiological context we have developed two different ALK knockout strains, the ALK Kinase knockout (KO) and the ALK exon1 KO. The only visible phenotype in these strains is a reduction of total body weight which is apparent in the ALK-/- population when compared to wild type littermates. This size difference seems to take place after birth and is not due to an alteration in food consumption. We have also extensively studied the ALK Kinase KO with respect to gross development, the gastrointestinal canal and the olfactory system. ALK displays a very distinct expression pattern within the gastrointestinal canal being confined to enteric neuron precursors during embryogenesis and enteric nerves in the adult tissue. From these studies we conclude that ALK is not needed for development and viability in mice although it does play a role in regulation of body weight via a presently unknown mechanism.

In addition, we have investigated the relationship between the Drosophila and mouse ALK receptor by examining the ability of the Drosophila Alk ligand Jelly-Belly, Jeb, to activate mouse ALK. Using different in vivo and in vitro techniques, we have shown that activation of mouse ALK cannot be accomplished by Drosophila Jeb. From this study we draw the conclusion that during development ligands for the Drosophila and mouse ALK has diverged to a level at which they can no longer substitute for each other.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2008. , 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1235
Keyword [en]
ALK, nervous system, knockout, development, Jelly-Belly
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1956ISBN: 978-91-7264-708-4 (print)OAI: oai:DiVA.org:umu-1956DiVA: diva2:142561
Public defence
2009-01-16, Betula, 6M, Norrlands universitets sjukhus, UMEÅ, 13:00 (English)
Opponent
Supervisors
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Characterization of the expression of the ALK receptor tyrosine kinase in mice.
Open this publication in new window or tab >>Characterization of the expression of the ALK receptor tyrosine kinase in mice.
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2006 (English)In: Gene Expression Patterns, ISSN 1567-133X, E-ISSN 1872-7298, Vol. 6, no 5, 448-461 p.Article in journal (Refereed) Published
Keyword
Animals, Antibody Specificity, Base Sequence, DNA Primers, Gene Expression Regulation; Developmental, Immunohistochemistry, In Situ Hybridization, Mice, Protein-Tyrosine Kinases/*genetics/immunology/metabolism, RNA; Messenger/genetics/metabolism
Identifiers
urn:nbn:se:umu:diva-15366 (URN)10.1016/j.modgep.2005.11.006 (DOI)16458083 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. The ligand Jelly Belly (Jeb) activates the Drosophila Alk RTK to drive PC12 cell differentiation, but is unable to activate the mouse ALK RTK
Open this publication in new window or tab >>The ligand Jelly Belly (Jeb) activates the Drosophila Alk RTK to drive PC12 cell differentiation, but is unable to activate the mouse ALK RTK
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2007 (English)In: Journal of experimental zoology, part B Molecular and developmental evolution, ISSN 1552-5007, Vol. 308, no 3, 269-282 p.Article in journal (Refereed) Published
Abstract [en]

The Drosophila Alk receptor tyrosine kinase (RTK) drives founder cell specification in the developing visceral mesoderm and is crucial for the formation of the fly gut. Activation of Alk occurs in response to the secreted ligand Jelly Belly. No homologues of Jelly Belly are described in vertebrates, therefore we have approached the question of the evolutionary conservation of the Jeb-Alk interaction by asking whether vertebrate ALK is able to function in Drosophila. Here we show that the mouse ALK RTK is unable to rescue a Drosophila Alk mutant, indicating that mouse ALK is unable to recognise and respond to the Drosophila Jeb molecule. Furthermore, the overexpression of a dominant-negative Drosophila Alk transgene is able to block the visceral muscle fusion event, which an identically designed dominant-negative construct for the mouse ALK is not. Using PC12 cells as a model for neurite outgrowth, we show here for the first time that activation of dAlk by Jeb results in neurite extension. However, the mouse Alk receptor is unable to respond in any way to the Drosophila Jeb protein in the PC12 system. In conclusion, we find that the mammalian ALK receptor is unable to respond to the Jeb ligand in vivo or in vitro. These results suggest that either (i) mouse ALK and mouse Jeb have co-evolved to the extent that mALK can no longer recognise the Drosophila Jeb ligand or (ii) that the mALK RTK has evolved such that it is no longer activated by a Jeb-like molecule in vertebrates.

National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-17925 (URN)10.1002/jez.b.21146 (DOI)17285636 (PubMedID)
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2010-10-15Bibliographically approved
3. The ALK KO display an idiopathic reduction of total body weight
Open this publication in new window or tab >>The ALK KO display an idiopathic reduction of total body weight
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3727 (URN)
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2010-01-13Bibliographically approved
4. ALK expression within the olfactory bulb
Open this publication in new window or tab >>ALK expression within the olfactory bulb
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3728 (URN)
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2010-01-13Bibliographically approved

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