TEAM

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.

FOR BEGINNERS

During embryonic development, brain neurons establish billion of connections by extending long processes called axons.

cône de croissance

Neuronal growth cones (in red) guide developing neurites.

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.

FOR SPECIALISTS

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.

Tumeur

Experimental breast tumor

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.


Main publications

PUBLICATION

Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers.

Luchino J, Hocine M, Amoureux MC, Gibert B, Bernet A, Royet A, Treilleux I, Lécine P, Borg JP, Mehlen P, Chauvet S, Mann F.
Cancer Cell. 2013 Nov 11;24(5):673-85. PMID: 24139859

PUBLICATION

Pathfinding of corticothalamic axons relies on a rendezvous with thalamic projections.

Deck M, Lokmane L, Chauvet S, Mailhes C, Keita M, Niquille M, Yoshida M, Yoshida Y, Lebrand C,Mann F, Grove EA, Garel S.
Neuron. 2013 Feb 6;77(3):472-84. PMID: 23395374

PUBLICATION

VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain.

Bellon A, Luchino J, Haigh K, Rougon G, Haigh J, Chauvet S, Mann F.
Neuron. 2010 Apr 29;66(2):205-19. PMID: 20434998

PUBLICATION

Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.

Niquille M*, Garel S*, Mann F*, Hornung JP, Otsmane B, Chevalley S, Parras C, Guillemot F, Gaspar P, Yanagawa Y, Lebrand C. * equal contribution
PLoS Biol. 2009 Oct;7(10):e1000230. PMID: 19859539

PUBLICATION

Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development.

Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F.
Neuron. 2007 Dec 6;56(5):807-22. PMID: 18054858

PUBLICATION

Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins.

Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD.
Science. 2005 Jan 14;307(5707):265-8. PMID: 15550623
Other publications

PUBLICATION

The Declaration of Independence of the Neurovascular Intimacy

Chauvet S, Mann F.
Neuron. 2013 Oct 16;80(2):262-5. PMID: 24139030

PUBLICATION

Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues.

Chauvet S, Burk K, Mann F.
Cell Mol Life Sci. 2013 May;70(10):1685-703. PMID: 23475066

PUBLICATION

Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.

Meadows SM, Fletcher PJ, Moran C, Xu K, Neufeld G, Chauvet S, Mann F, Krieg PA, Cleaver O.
Circ Res. 2012 Jan 6;110(1):34-46. PMID: 22076636

PUBLICATION

Semaphorin 3C is not required for the establishment and target specificity of the GABAergic septohippocampal pathway in vitro.

Rubio SE, Martínez A, Chauvet S, Mann F, Soriano E, Pascual M.
Eur J Neurosci. 2011 Dec;34(12):1923-33. PMID: 22092651

PUBLICATION

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.

Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A.
J Clin Invest. 2011 May;121(5):1974-85. PMID: 21505259

PUBLICATION

PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla.

Choi YI, Duke-Cohan JS, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL.
Immunity. 2008 Dec 19;29(6):888-98. PMID: 19027330

PUBLICATION

Mechanisms of axon guidance: membrane dynamics and axonal transport in semaphorin signalling.

Mann F, Rougon G.
J Neurochem. 2007 Jul;102(2):316-23. PMID: 17442048

PUBLICATION

Semaphorins in development and adult brain: Implication for neurological diseases.

Mann F, Chauvet S, Rougon G.
Prog Neurobiol. 2007 Jun;82(2):57-79. PMID: 17537564

PUBLICATION

A semaphorin code defines subpopulations of spinal motor neurons during mouse development.

Cohen S, Funkelstein L, Livet J, Rougon G, Henderson CE, Castellani V, Mann F.
Eur J Neurosci. 2005 Apr;21(7):1767-76. PMID: 15869472

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

Interactions

IBDM
NATIONAL
  • Annie Andrieux, GIN
  • Alice Davy, CBD
  • Sonia Garel, IBENS
  • Patrick Mehlen, CRCL
  • Michèle Studer, IBV
  • Jean-Léon Thomas, ICM
INTERNATIONAL
  • Jody Haigh, VIB, Belgium
  • Atsushi Kumanogoh, Osaka University, Japan
  • Cécile Lebrand, Lausanne University, Switzerland
  • Christiana Ruhrberg, University College London, GB
  • Michael Simons, Yale University, USA

Lab Twitter


Funding

ANR

FRC

institutcancer

IUF

Members more

Mike Altounian Anaïs Bellon Sophie Chauvet     Mélanie Hocine-ducros   Thi trang huyen Nguyen Theodora Velona
Fanny Mann
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Fanny Mann

Researcher

Mike Altounian
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Mike Altounian

PhD student

Anaïs Bellon
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Anaïs Bellon

University lecturer

Sophie Chauvet
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Sophie Chauvet

University lecturer

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Micaela De Pina Roque

PhD student

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Jérémy Guillot

PhD student

Mélanie Hocine-ducros
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Mélanie Hocine-ducros

Technical staff

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Adrien Lucchesi

PhD student

Thi trang huyen Nguyen
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Thi trang huyen Nguyen

PhD student

Theodora Velona
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Theodora Velona

PhD student

Alumni

  • Samia Cohen
  • Anaïs Bellon
  • Jonathan Luchino

Overview

Model organism
Biological process studied
  • Cellular interactions, signaling and receptor trafficking, axon guidance, tumor progression
Technical approaches
  • Cellular and molecular biology
  • Biochemistry
  • Immunohistochemistry, in situ hybridization
  • Neuron primary culture
  • Microfluidic cell culture
  • Time-lapse imaging
  • Behavioral tests
  • Tumor grafts
  • Transgenic mouse lines
Medical applications
  • Neurodevelopmental diseases, traumatic brain injuries and cancer