Multistep mechanisms of Wnt signaling in asymmetric habenular neural circuit establishment
Molecular and Cellular Neurology and Neuropathology
Final Report Abstract
Bilateral clusters of habenular neurons in the forebrain of vertebrates relay cognitive information into the interpeduncular nucleus and the median raphe in the ventral mid- and hindbrain, respectively. This neurotransmitter system has been implicated in behaviours from fear and social behaviour to reward responses and addiction. It is also linked to pathophysiological syndromes such as depression, autism and schizophrenia. Our studies in zebrafish have revealed that the Wnt/beta-catenin signalling pathway gene Tcf7l2 is pivotal for the establishment of habenular neuron diversity. We now find that premature activation of Wnt signalling delays habenular neuron differentiation, severely perturbs correct habenular neuron identities and abrogates the laterotopic segregation of habenular efferent axons in the IPN target. Our gene expression and functional analysis provide strong evidence that the secreted tumour suppressor Wnt inhibitory factor 1 (Wif1) is mediating the temporal control of Wnt signaling. Once initiated, Wif1 expression in turn depends on Wnt signaling itself similar to findings in cancer cells in vitro suggesting a conserved mechanism underlying different processes. The knowledge gained with this project enables us now to generate fish with defined aberrations in the habenulae for analysing the impact on behavior. Intriguingly, malfunction of the habenular neural circuit being involved in a number of brain disorders such as autism spectrum disorder, depression, schizofrenia and drug addiction. Progress in developing therapies has been slow and new therapeutical targets are needed to help patients exhibiting severe forms of depression or those that are medication resistant. To improve life quality, innovative alternative approaches for therapy development are required. Moreover, two of the genes we identified to control habenular neuron type formation, Tcf7l2 and Wif1, have been linked to schizophrenia and autism, paving the path for further exploring the link between molecule, neural circuit and pathophysiological syndrome. We now apply in vivo HTS to identify candidate therapeutic compounds 1.) impacting habenula development and habenular neuron differentiation and 2.) having an ameliorating effect on habenular neuron malformation and malfunction. The project also increased the visibility of my work for the general public by generating articles published on the University’s homepage (https://pressroom.unitn.it/comunicato-stampa/molecule-directs-neurons) as well as the local press (https://www.ansa.it/trentino/notizie/2020/03/17/individuata-molecola-percorretta-sinfonia-neurale_0f0d8d5c-ad99-46d0-b984-58a24ee01965.html).
Publications
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Temporal control of Wnt signaling is required for habenular neuron diversity and brain asymmetry. Development. 2020;147(6):dev182865
Guglielmi L., Bühler A., Moro E., Argenton F., Poggi L., Carl M.
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Zebrafish Tools for Deciphering Habenular Network-Linked Mental Disorders. Biomolecules. 2021; 11(2):324
Bühler A., Carl M.
