TEAM

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.

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.

 


Selected publications

PUBLICATION

Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons.

Mire E, Hocine M, Bazellières E, Jungas T, Davy A, Chauvet S, Mann F.
Curr Biol. 2018 Jun 4;28(11):1768-1782.e4. doi: 10.1016/j.cub.2018.04.026. PMID: 29779877

PUBLICATION

Post-endocytic sorting of Plexin-D1 controls signal transduction and development of axonal and vascular circuits

Burk K, Mire E, Bellon A, Hocine M, Guillot J, Moraes F, Yoshida Y, Simons M, Chauvet S, Mann F.
Nat Commun. 2017 Feb 22;8:14508. doi: 10.1038/ncomms14508. PMID: 28224988

PUBLICATION

Characterizing Semaphorin Signaling Using Isolated Neurons in Culture

Chauvet S, Mire E, Mann F.
Methods Mol Biol. 2017;1493:223-235. PMID: 27787854

PUBLICATION

Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

Deloulme JC, Gory-Fauré S, Mauconduit F, Chauvet S, Jonckheere J, Boulan B, Mire E, Xue J, Jany M, Maucler C, Deparis AA, Montigon O, Daoust A, Barbier EL, Bosc C, Deglon N, Brocard J, Denarier E, Le Brun I, Pernet-Gallay K, Vilgrain I, Robinson PJ, Lahrech H, Mann F, Andrieux A.
Nat Commun. 2015 Jun 3;6:7246. doi: 10.1038/ncomms8246. PMID: 26037503

PUBLICATION

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Cariboni A, André V, Chauvet S, Cassatella D, Davidson K, Caramello A, Fantin A, Bouloux P, Mann F, Ruhrberg C.
J Clin Invest. 2015 Jun;125(6):2413-28. doi: 10.1172/JCI78448. PMID: 25985275

PUBLICATION

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

Bribián A, Nocentini S, Llorens F, Gil V, Mire E, Reginensi D, Yoshida Y, Mann F, del Río JA2.
Nat Commun. 2014 Jun 27;5:4265. doi: 10.1038/ncomms5265. PMID: 24969029

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

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

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

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

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

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

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

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

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

PUBLICATION

Neuropilin-dependent and -independent signaling of the guidance molecule Sema3E

Mann F, Chauvet S.
Neufeld G, Kessler O (Eds.) The Neuropilins: Role and Function in Health and Disease. 2017. Springer International Publishing. p.75-89

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

NATIONAL
  • Annie Andrieux, GIN
  • Emmanuel Barbier, GIN
  • Alice Davy, CBD
  • Sonia Garel, IBENS
  • Patrick Mehlen, CRCL
  • Richard Tomasini, CRCM
INTERNATIONAL
  • Jody Haigh, VIB, Belgique
  • Cécile Lebrand, Université de Lausanne, Suisse
  • Christiana Ruhrberg, University College London, GB
  • Michael Simons, Yale University, USA
  • Marta Nieto, CNB, Spain

Lab Twitter


Funding

ANR

FRC

institutcancer

IUF

Imprimer

Logo FRM

Logo canceropole

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Members more

Mike Altounian Sophie Chauvet     Jérémy Guillot Mélanie Hocine-ducros
Fanny Mann
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Fanny Mann

Researcher

Mike Altounian
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Mike Altounian

PhD student

Sophie Chauvet
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Sophie Chauvet

University lecturer

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Micaela De Pina Roque

PhD student

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Chloe Dominici

Technical staff

Jérémy Guillot
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Jérémy Guillot

PhD student

Mélanie Hocine-ducros
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Mélanie Hocine-ducros

Technical staff

Alumni

  • Samia Cohen
  • Jonathan Luchino
  • Marion Benezech
  • Katja Burk
  • Laura Miranda
  • Erik Mire

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