Axon plasticity in development and cancer
Group leader : F. Mann
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.
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.
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
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.
June 4th, 2018
Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons.
February 22nd, 2017
Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits
October 28th, 2016
Characterizing Semaphorin Signaling Using Isolated Neurons in Culture
June 3rd, 2015
Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth
May 18th, 2015
Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
June 27th, 2014
Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex
November 11th, 2013
Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers.
October 16th, 2013
The Declaration of Independence of the Neurovascular Intimacy
May 1st, 2013
Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues.
February 1st, 2013
Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.
January 1st, 2012
Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.
December 1st, 2011
Semaphorin 3C is not required for the establishment and target specificity of the GABAergic septohippocampal pathway in vitro.
May 1st, 2011
Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.
April 1st, 2010
VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain.
October 1st, 2009
Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.
December 1st, 2008
PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.
December 1st, 2007
Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.
July 1st, 2007
Mechanisms of axon guidance: membrane dynamics and axonal transport in semaphorin signalling.
June 1st, 2007
Semaphorins in development and adult brain: Implication for neurological diseases.
April 1st, 2005
A semaphorin code defines subpopulations of spinal motor neurons during mouse development.
January 1st, 2005
Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.
January 15th, 2017
Neuropilin-dependent and -independent signaling of the guidance molecule Sema3E
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