| 1. |
- Vernersson Lindahl, Emma, 1980-
(författare)
-
Investigating the function of Anaplastic Lymphoma Kinase
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
