The Flamingo ortholog FMI-1 and the CDK8 Mediator subcomplex regulate axon navigation in Caenorhabditis elegans

The nervous system is a highly complex organ system that controls the body’s physiology and behaviour. It is our place of thought and consciousness. Neurons are the functional units of the nervous system, which send out cellular processes, dendrites and axons, to connect to other neurons and muscle cells. The correct interconnection of neurons or neurons and muscles is of critical importance for nervous system function. Neuronal circuits are established during embryonic development, when neuronal processes navigate to their target areas and establish synapses with appropriate partner cells. Early outgrowing axons (pioneers) establish the main axon tracts. Later outgrowing axons (followers) frequently extend along these previously established axon tracts. We use the roundworm Caenorhabditis elegans to identify and characterize novel genes regulating axon pathfinding. The aim of this study was to identify and characterize two genes previously isolated in genetic screens for axonal defects. The first was identified as the ‘non-classical’ cadherin FMI-1, a member of the cadherin superfamily of cell adhesion molecules. Loss of FMI-1 caused strong axon navigation defects of pioneer and follower axons in the ventral nerve cord. Follower axons, which exclusively depend on pioneer axons for correct navigation, frequently separated from the pioneer, defining a novel role for this highly conserved molecule. We found that follower axon navigation depended on the extracellular but not on the intracellular domain, suggesting that FMI-1 primarily mediates adhesion between pioneer and follower axons. The study of FMI-1, presented in chapter two, contributes to our understanding of the molecular basis of pioneer-mediated navigation of follower axons. The second gene encoded a subunit of the Mediator of transcriptional regulation, LET-19/MDT-13. Further analysis revealed that several Mediator subunits, including the complete CDK8 subcomplex, participate in regulating axon navigation in subsets of neurons. Mutations in Mediator subunits likely change the expression of genes required for correct axon navigation. For example, during dorsal navigation of motoneuron axons, the Mediator complex is required to suppress the function of the SAX-3/ROBO guidance receptor. These results, described in chapter three, highlight the importance of transcriptional control for correct axon navigation.