The mature nervous system is an intricate network in which neurons are connected to specific partners. The choice of these partners is crucial for the correct behavior of the network (meaning the nervous system) and is determined at early stages of development. Abnormal development of neuronal connections is responsible for a large range of neuronal pathologies, some of them affecting vision. The research lines of our team focus on a better understanding of the development of sensory maps including the connection between the retina and the brain. We aim at identifying the intracellular pathways guiding retinal axons towards their targets in the brain and shaping their terminal arbors. We focus on signals required for axons to detect and interpret attractive and repulsive cues from their environment or involved in axon branching and pruning.
Cyclic nucleotides (cAMP and cGMP) and calcium are crucial for axons to integrate extracellular signals required for axon pathfinding. They are also involved in a wide range of signaling pathways that do not influence axon guidance. We aim at decrypting the codes used by axons to identify such cellular messenger signals as specific regulators of neuronal connectivity. We investigate the spatial and temporal features of cyclic nucleotide and calcium signals to understand how these ubiquitous molecules achieve specificity for their downstream pathways controlling the pathfinding of developing axons.
We use a combination of anatomical, imaging and optogenetic techniques to investigate the role of second messengers in the development of sensory maps. FRET imaging enables following cellular messenger concentration in living cells. Other techniques including subcellular targeting of genetically-encoded cAMP, cGMP and calcium buffers, and the use of light sensitive tools (optogenetics) make possible precise manipulations of these signals in time and space. Using these tools we are able to test the importance of local and temporal coding of cellular signals during the development of neuronal networks.
The control of cell adhesion is critical for developing axons to grow, change their outgrowth direction or retract. We investigate the signaling pathways linking axon guidance molecules and their integration by second messengers to the modulation of cell adhesion.
TIRF imaging, combined with alteration of adhesion site-specific manipulation of signaling events is used to evaluate how signaling molecules integrating guidance cues signals modulate the events occurring at adhesion sites in the growth cone of developing axons.
Axon pathfinding requires a tight control of actin and microtubule cytoskeletons. Fidgetin-like 1 is a critical regulator of microtubule depolimerization and controls the behavior of developing axons. We explore how Fidgetin-like 1 interacts with the signaling of axon guidance molecules to control the remodeling of actin and microtubule cytoskeletons during axon pathfinding.
This project combines live imaging, cell culture and biochemical approaches to investigate the dynamic events remodeling actin and microtubules. In vivo approaches using both zebrafish and mouse models are also used to evaluate the influence of Fidgetin-like 1 on developing axons in an intact organism.
Once axonal arbors are coarsely organized in their targets, complex and activity-dependent interactions between axons lead to the elimination of exuberant branches and synapses, while appropriate contacts are stabilized. This process requires interactions between neighboring axons. We investigate these interactions that influence the refinement of their terminal arbor.
We used an approach enabling to manipulate signaling events or electrical activity in a subset of retinal ganglion cells in vivo, and to simultaneously trace the axons of their neighbors with intact signaling and activity. This enables to evaluate how neighboring neurons interact while their exuberant and immature axonal arbors is pruned.
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