Wnt proteins are a highly conserved family of signaling molecules that play a central role during development and in adult tissue homeostasis. Wnt proteins regulate a variety of biological processes, ranging from cell proliferation and cell fate determination to cell migration, axon guidance and synapse formation. To mediate these functions, Wnt proteins trigger different intracellular signal transduction pathways. We have used the nematode Caenorhabditis elegans as a model system to study the mechanism of Wnt signaling. The advantage of this relatively simple model organism is that it enables us to study Wnt signaling at single cell resolution. In chapter 2 we describe a genetic screen for mutants that affect the EGL-20/Wnt dependent migration of the Q neuroblasts. As part of this study, we describe three new loci that may encode novel components of the canonical Wnt/β-catenin pathway. In chapter 3, we describe the function of the Axin-like protein AXL-1 in this pathway. We show that AXL-1 functions redundantly with the Axin-like protein PRY-1 in Q neuroblast migration and vulva development and independently of PRY-1 in a canonical Wnt/β-catenin pathway that is required for excretory cell development. Even though their functions partially overlap, AXL-1 and PRY-1 are not equivalent. We have previously shown that the functions of β-catenin are distributed over different β-catenin proteins in C. elegans. Our results suggest that AXL-1 and PRY-1 may represent another example of such functional diversification. In addition to studying signaling downstream of Wnt, we have also investigated the still poorly understood mechanism of Wnt secretion. Our group has previously shown that an intracellular protein sorting complex, called the retromer, is required in Wnt producing cells. One of the known functions of the retromer complex is the retrograde transport of specific membrane proteins from endosomes to the Golgi. In chapter 4, we show that the recently identified Wnt binding protein Wntless is a target of retromer dependent sorting. In the absence of retromer function, Wntless is degraded in lysosomes and becomes limiting for Wnt signaling. Future studies will determine how sorting and secretion of Wnt is mediated by Wntless and how this process is regulated by the retromer complex.
|Originele taal-2||Niet gedefinieerd|
|Kwalificatie||Doctor of Philosophy|
|Datum van toekenning||28 jan 2008|
|Plaats van publicatie||Amsterdam|
|Status||Gepubliceerd - 2008|