Multistep mechanisms of Wnt signaling in asymmetric habenular neural circuit establishment

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Neuronal populations are usually established similarly on both sides of the brain. They form networks by extending axons which connect different brain areas and allow for the flow of information. A failure in these processes can have devastating consequences for the organism. These bilateral structures frequently differ between the two hemispheres in their anatomy and connectivity as well as in their function. If and how these asymmetric features are linked and may influence our daily life and behavior is a long-standing question in Neuroscience. One such left-right asymmetric network, named habenular neural network, has recently been established in the zebrafish (Danio rerio) as model system for studying this question of functional lateralization of the brain. During habenular development, the Wnt signaling cascade influences the generation of the different types of neurons the habenulae are made of. Preliminary data suggest that in this process the Wnt signals need to be precisely controlled in time. If this timing is disrupted, one habenular neuron subtype is not generated and the habenulae develop left-right symmetric. The molecule mediating this temporal control may be the secreted Wnt inhibitory factor 1 (Wif1), which shows specific expression in habenular precursor cells just around the time the habenular neurons are specified. Intriguingly, Wif1 also appears to act in a regulatory feedback loop on its own expression. My aim is to assess this novel mechanism of temporal control of Wnt signaling during neurogenesis and the establishment of brain asymmetry. Further preliminary experiments suggest that Wnt signals may also be involved in the subsequent pathfinding of habenular efferent axons. How these axons find their way through the brain has remained unknown and the data suggest that Wnt is controlling so far not revealed guidance factors. Therefore, the second aim of my project is to determine the role of Wnt signaling in axon guidance and to uncover the factor(s) involved. The gained knowledge will further allow to introduce defined, non-invasive subtle alterations into the asymmetric brain on the neuronal and the axonal level. This in turn will facilitate the study of functional consequences of network manipulations in adult animals.Taken together, the conserved habenular neurotransmitter system of the zebrafish has emerged as a powerful model to investigate the generation of neuronal diversity, axonal pathfinding and left-right asymmetric function in the vertebrate brain. Preliminary data suggest that temporal control of Wnt signaling plays a crucial role in the differentiation and axonal pathfinding of habenular neurons. Manipulation of this signaling cascade will shed light not only on how the habenular network develops but also on the genesis of pathophysiological syndromes and various behaviors. Thus, my work is likely to have widespread impact in- and outside the fields of Developmental Biology and Neuroscience.