Axon guidance in the mammalian brain
Group leader : F. Mann
We study how neurons connect with each other during embryonic development to form complex communication networks that underlie our emotions, thoughts and behaviors.
During embryonic development, brain neurons establish billion of connections by extending long processes called axons.
Their growth is not random, but precisely oriented, guided by molecules located in the cellular environment through which the axon grow. We seek to understand how axons detect and interpret these signals, and how fine regulations that are involved in individual responses to guidance molecules can control both the accuracy and the wide diversity of axonal trajectories. To address this problem, we use the embryonic mouse brain as a model. Our analyses focus on different nerve fiber bundle conserved in mammalian : the long-range projections connecting the left and right hemispheres of the brain (corpus callosum, anterior commissure) or connecting distant structures within the same hemisphere (fornix). Axon guidance molecules are present in various tissues and organs during development but also in adults where their expression can be reactivated under various pathological conditions (neurological disorders, cancers). Thus, understanding the mechanisms of axon guidance extends beyond the field of neural development and constitutes a prerequisite step toward the development of new tools for diagnostic or therapy.
Our recent studies have focused on the Semaphorin (Sema) family of molecules in the control of axonal guidance and have enabled us to highlight the influence of two members of this protein family, Sema3C and Sema3E, in the establishment of major brain fiber tracts. It emerged that Semaphorins have a dual effect, attracting or repelling axon growth depending on the type of neuron on which they act. An in-depth study of the mode of action of Sema3E revealed that a key determinant of this bifunctionality is the composition of the receptor complex. Thus, the repulsive action of Sema3E is initiated by its binding to the surface receptor Plexin-D1, while its attractive action is exerted via the recognition of a trimeric complex including, in addition to Plexin-D1, Neuropilin-1 and VEGFR2 (vascular endothelial growth factor receptor 2 ) proteins. This result further showed that the VEGFR2 molecule, first known for its role in the development of another vital network – the vascular system, is also a key player in the establishment of neuronal circuits.
Current research is directed towards three main areas :
1) Membrane trafficking and in particular the endocytosis / exocytosis events are key factors in the regulation of responses to axon guidance signals. However, the endocytic patterns of activated receptors, the fate of receptors following their internalization and the molecular mechanisms regulating their trafficking remain largely misunderstood. We address these questions by studying the control of Semaphorin receptor trafficking by PDZ domain-containing molecules, which are often chosen as therapeutic targets in nervous system disorders.
2) We want to know the dynamic sequence of cellular and molecular events leading to the formation of major axon tracts in the mammal brain. For this, we develop ex vivo models that allow time-lapse imaging of growing axons in their natural environment and evaluation, in living tissue, of the effect of signaling pathways previously characterized on the dynamic behavior of axons.
3) Efforts are being made to transfer our knowledge and expertise from the study of axon guidance molecules to the field of cancer where these signaling pathways are frequently deregulated. This work has recently led to identification of a compound that inhibits Sema/Plexin-D1 interaction and shows anti-cancer activity in pre-clinical models. These results have been the subject of a patent application.
November 11th, 2013
Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers.
February 1st, 2013
Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.
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, 2007
Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.
January 1st, 2005
Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.
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.
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.
December 1st, 2008
PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.
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.
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