Our group focuses on how activated receptors transmit their signals within neurons, an essential process during development and – if this process is failing- in neurodegeneration.
During the development of neural circuits, neurites grow toward their targets guided by cues in the extracellular environment. These cues are sensed by receptors at the surface that trigger intracellular signaling event, modulating the cytoskeleton. This direction-mediated process allows neurons to find and innervate their appropriate targets in order to form functional synapses. Remarkably, our nervous system contains trillions of connections but only a few hundred growth/guidance cues. Therefore, one important question is how this small number of cues coordinates the wiring of a disproportionally large number of connections. This process is regulated through diversification- a mechanism that amplifies the number of signaling decisions a neuron can make. For example, we found that receptors are able to change their downstream signaling targets over time, which allows adaptation to the required developmental demands. Further, diversification can also occur on the level of endosomes. Here, receptors can be re-routed from one endosomal pathway into another and therefore regulate different functional outcomes (e.g. ensuring neuronal survival vs synapse maturation).
Diversification can also occur through retrieval versus degradation of receptors. While the signaling of some receptors is terminated through degradation, other receptors are retrieved from the degradative pathway in order to start their signaling. This mechanism ensures that receptors only signal at specific locations (e.g. at the soma or at the distal end).
Another mechanism which we study is the integration of signaling. While diversification amplifies the number of signalling decisions, integration merges signalling pathways which eventually affect the level of the cytoskeleton. The cytoskeleton is a key regulator in trafficking as it ensures movement of cargo from distal to proximal ends and back. Defects of the cytoskeleton affect trafficking in neurons- but also signaling from e.g. trophic receptors affect the stability of the cytoskeleton. Therefore, when studying receptor sorting and signaling, we study the effects on the cytoskeleton at the same time.
Our findings are then applied translationally to study neurodegenerative diseases such as Charcot-Marie-Tooth disease and Amyothrophic Lateral Sclerosis.
To answer the above questions, we use model systems such as primary neurons from mouse and chick, iPSC-derived sensory and motor neurons and apply several imaging techniques (e.g. confocal, total internal reflection fluorescence (TIRF), stimulated emission depletion (STED), electron- or spinning-disk microscopy) and biochemistry.