Our team is studying how neurons wire together during the development of the nervous system and how neuronal circuits are reorganized in organs affected by cancer.

FOR BEGINNERS

One of our model is the corpus callosum, an axon tract that interconnects the left and right hemispheres of the brain (here visualized in a mouse embryo)

Normal brain function depends on complex patterns of neuronal circuits that develop during fetal life and childhood. Several neurological disorders result from alterations that occur during the construction of brain networks.

Neurons connect to each others by extending long cables, called axons, whose growth is not random but precisely oriented towards their targets by axon guidance molecules. Our team studies the mechanisms that contribute to the fine regulation of guidance cue activities to ensure the accuracy and fidelity of axonal trajectories.

In addition to being essential to brain development, axon guidance molecules are also present in adult organisms where their expression can be reactivated under pathological conditions such as cancer. We are investigating whether their activity could contribute to the innervation of malignant tumors, a process that is still poorly characterized but can influence the course of the disease.

FOR SPECIALISTS

1.Combinations of receptors and multiplicity of axonal responses

Our previous work has highlighted multiple roles played by axon guidance molecules of the Semaphorin family in axonal development. It emerged that Semaphorins have a dual effect, attracting or repelling axon growth depending on the neuron type. We have shown that an essential determinant of this bi-functionality is the composition of the receptor present on the axonal surface. Thus, the repulsive action of the Semaphorin-3E (Sema3E) is initiated by its binding to the Plexin-D1 receptor, while its attractive action is exerted via the recognition of a trimeric complex including, in addition to Plexin-D1, Neuropilin-1 and VEGFR2 proteins (Gu et al., 2005, Chauvet et al., 2007, Bellon et al., 2010). These results were the basis for a collaboration with the laboratory of Annie Andrieux (Grenoble Institute of Neurosciences) that identified a defect in neuronal connectivity due to a loss of attractive Sema3E signaling activity in a mouse model of schizophrenia (Deloulme et al., 2015). 

2. Trafficking and signaling of axon guidance receptors

Local endocytosis at growth cones plays a key role in responses to axon guidance cues. Yet, little is known about the fate of internalized surface receptors. Our team has shown that the Plexin-D1 receptor contains a sorting motif that interacts with the adaptor protein GIPC1 to facilitate transport to recycling endosomes. This process promotes co-location of Plexin-D1 with vesicular pools of active R-ras and allows the initiation of PlexinD1 signaling from recycling endosomal compartments. This mechanism has important implications for cerebral development since the loss of GIPC1 leads to structural abnormalities of neural circuits (Burk et al., 2017). This project is pursued by the study of other molecules regulating the intracellular trafficking of receptors and also known for their implication in neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.

3. Axon guidance cues and cell death in cancer

We use our knowledge and expertise on the biology of axon guidance cues to investigate their roles in cancer. This work provided evidence that Sema3E promotes cell survival by inhibiting a death pathway induced by a Plexin-D1/Nr4a1 complex. In mouse models of breast cancer, we showed that a “ligand-TRAP” that sequesters Sema3E reduces tumor growth and metastasis through a tumor cell-specific cytotoxic effect. These results defined a critical role of Sema3E in tumor resistance to programmed cell death and suggested a novel therapeutic approach for cancer (Luchino et al., 2013). These findings are now exploited by the biotechnology company Netris Pharma (Lyon, France).

4. Axonal remodeling in cancer

3D reconstruction of the neuronal (red) and vascular (green) networks in pretumoral lesions (blue) of the mouse pancreas.

Clinical observations have revealed the presence of axonal fibers in many types of cancers, consistent with high levels of certain axon guidance molecules in tumors. This suggests that mature neurons can infiltrate tumors in a process termed tumor-induced axonogenesis. We are currently using 3D imaging combined with tissue clearing techniques to characterize structural changes in the innervation of organs affected by cancer. We are also identifying the axon guidance signaling pathways that promote this axonal plasticity with the aim to stop this process and study its impact on the evolution of cancer.

NETRIS PHARMA, CNRS, AMU. Antagonists of Sema3E/PlexinD1 interaction as anti-cancer agents. ROYET Amélie, MANN Fanny, CHAUVET Sophie, LUCHINO Jonathan. EPO Patent. EP2385121 (A1). 2010-05-06