Genetic control of left/right asymmetry in C. elegans neuroblast migration

TY - THES

T1 - Genetic control of left/right asymmetry in C. elegans neuroblast migration

AU - Middelkoop, T.C.

PY - 2014/9/22

Y1 - 2014/9/22

N2 - The migration of cells is crucial for proper animal development. In order to study cell migration in an in vivo context we used the small nematode C. elegans as a model organism. During C. elegans larval development two Q neuroblasts, initially positioned on equivalent left/right positions, migrate in opposite directions along the anteroposterior axis. Previous studies showed that the Wnt target gene mab-5 is expressed in a left/right asymmetric manner and that it is essential for the left/right asymmetric migratory behavior. In this thesis we studied a variety of aspects of the left/right asymmetric migration of Q neuroblasts. First, we showed that a combination of positive and negative transcriptional feedback interactions within the Wnt pathway results in activation of mab-5 expression to a stable range exhibiting low expression variability. Furthermore, the initial polarization of Q neuroblasts that precedes Wnt signaling activation was found to be necessary for the proper left/right asymmetric mab-5 expression. While analyzing mutants in which the initial polarization was affected we found that posterior initial polarization positively correlates with the upregulation of mab-5 expression. Finally, we showed that several genes encoding transmembrane proteins act together in partially overlapping genetic pathways to ensure proper initial Q neuroblast polarization. The studies described in this thesis have provided a basic genetic framework that controls the initial Q neuroblast polarization and unraveled how proper initial polarization results in the robust left/right asymmetric expression of the Wnt target gene mab-5.

AB - The migration of cells is crucial for proper animal development. In order to study cell migration in an in vivo context we used the small nematode C. elegans as a model organism. During C. elegans larval development two Q neuroblasts, initially positioned on equivalent left/right positions, migrate in opposite directions along the anteroposterior axis. Previous studies showed that the Wnt target gene mab-5 is expressed in a left/right asymmetric manner and that it is essential for the left/right asymmetric migratory behavior. In this thesis we studied a variety of aspects of the left/right asymmetric migration of Q neuroblasts. First, we showed that a combination of positive and negative transcriptional feedback interactions within the Wnt pathway results in activation of mab-5 expression to a stable range exhibiting low expression variability. Furthermore, the initial polarization of Q neuroblasts that precedes Wnt signaling activation was found to be necessary for the proper left/right asymmetric mab-5 expression. While analyzing mutants in which the initial polarization was affected we found that posterior initial polarization positively correlates with the upregulation of mab-5 expression. Finally, we showed that several genes encoding transmembrane proteins act together in partially overlapping genetic pathways to ensure proper initial Q neuroblast polarization. The studies described in this thesis have provided a basic genetic framework that controls the initial Q neuroblast polarization and unraveled how proper initial polarization results in the robust left/right asymmetric expression of the Wnt target gene mab-5.

KW - Neuroblast migration, gene expression, Wnt signaling, live imaging, Caenorhabditis elegans

M3 - PhD thesis

PB - Utrecht University

ER -