Our lab is studying neuronal development in C. elegans. We are focussing on the question of how neuronal circuits are formed. Projects in the lab currently use various complementary approaches to identify and study genes involved in pathfinding of neuronal processes (axon guidance).
Screens for axon guidance mutants
We use different approaches to identify genes controlling axon navigation. In genetic screens animals are mutagenized, which randomly destroys genes. Progeny with defective axon navigation can be identified in live animals when neurons are labelled with fluorescent markers like the green fluorescent protein (GFP). We collected a number of mutants in novel genes with defects ranging from subtle fasciculation defects within the ventral cord to severe defects affecting axon navigation in various parts of the nervous system (see Figure). The detailed characterization of those genes will lead to new insights into the genetic control of axon outgrowth. In a complementary approach we use double stranded RNA mediated gene silencing (RNAi) in large-scale screens to identify novel axon guidance genes.
The role of pioneer neurons in axon guidance
Neuronal processes do not grow out simultaneously from all neurons. There is a distinct set of neurons, pioneers, who are the first to send out their axons. These form the starting point for the major axon tracts and provide a first scaffold of pathways that are populated by all the later outgrowing axons (followers). It is thought that the pioneer axons provide crucial navigation information for later outgrowing axons. This idea can be easily tested in C. elegans, where individual cells can be eliminated by a method termed 'laser ablation'. In the absence of certain pioneer neurons, later outgrowing axons indeed commit navigation errors (see Figure), but they are not completely lost and many of them still find their way to their targets. In other words pioneer neurons do not seem to be absolutely essential, but provide one (or more) of many different navigation cues for later outgrowing axons. Currently we are trying to identify genes involved in pioneer-mediated axon navigation in an attempt to understand this process at the molecular level.
IgCAMs and Cadherins in neuronal development
Several protein families are known to contain cell adhesion molecules and receptors important for neuronal development and axon guidance in particular. The largest families of this kind are IgCAMs (see figure) and cadherins. Many members of these families are evolutionary old and found in virtually every animal including C. elegans and humans. The function of the molecules often has changed very little even over evolutionary time scales (millions of years). A detailed analysis of the function of these proteins in a simple animal like C. elegans typically gives important clues for the role of these proteins in general. Some of the human counterparts of these proteins are known to be involved in diseases. By studying these genes our research not only sheds light on the molecular basis of fundamental aspects of neuronal development, it also contributes to the understanding of human diseases at the cellular and molecular level.