cycle 5 project 5

Characterization of the molecular interactors of SynCAM/CADM1 during neural circuit formation

 

P05-RaiPhD student: Surya Prakash Rai, Nepal
Home Institute: Neuroscience Center Zürich; Principle Investigator: Esther Stoeckli
Host Institute: Bordeaux Neurocampus; Principle Investigator: Nathalie Sans
2nd Host Institute: Amsterdam Neuroscience;  Principle Investigator: Ruud Toonen

Executive Summary

Neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, or intellectual disability, are characterized by aberrant neuronal connectivity. Mostly, the focus is put on synaptic plasticity that is reduced in patients compared to healthy subjects. However, the long lists of candidate genes associated with these neurodevelopmental disorders by genome-wide association studies or linkage analyses include a number of genes with a role in axon guidance. Furthermore, some of the genes identified for a role in synaptogenesis or synaptic plasticity have also been implicated in earlier aspects of neural circuit formation.
One of these genes is CADM1/SynCAM1. SynCAMs were identified based on their potential to induce synapses. Later, their contributions to myelination and synaptic plasticity were discovered. However, a role for SynCAMs in axon guidance has also been demonstrated. As found typically for members of the immunoglobulin-superfamily of cell adhesion molecules, SynCAMs exhibit a very complex interaction pattern. In addition to the published homophilic cis-interaction, we found also evidence for heterophilic cis-dimers which can modulate heterophilic trans-interactions, and therefore, fine-tune cell-cell contacts.
Intracellularly, SynCAMs were shown to interact with the synaptic scaffold molecules of the MAGUK family, such as CASK. So far, these molecules have not yet been implicated in early aspects of neural circuit formation. However, preliminary evidence obtained in our in vivo studies suggests that at least CASK is involved in axon guidance in the developing neural tube.

An important aspect of axonal behavior during pathfinding is the switch of responsiveness at intermediate targets. Along their trajectory, axons navigate from one intermediate target, or choice point, to the next, until they hit their final target. At each choice point, axons change from attraction to repulsion in order to move on to the next intermediate or their final target. The switch in responsiveness requires a change in surface receptors on the navigating growth cone. This can be achieved by different mechanisms. In addition to transcriptional changes, as found for commissural axons in response to Shh derived from the ventral midline, axons can use selective vesicle trafficking to insert axon guidance receptors in a precisely controlled manner into the growth cone surface once they have come in contact with the intermediate target. The position of membrane insertion and the regulatory details of vesicle transport and fusion with the plasma membrane are unknown. However, there is a good chance that CASK or MAGUKs in general play a role in determining the positioning of SynCAMs not only during synaptogenesis and synaptic plasticity but also during axon guidance.
In collaboration with Nathalie Sans, we explore the role of MAGUKs in axon guidance downstream of SynCAMs. In particular, we will study the contribution of these scaffold molecules to axon guidance using both the chicken and the mouse as model organisms. Finally, we will use imaging techniques to look at vesicular transport in cultured neurons in collaboration with Ruud Toonen.

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