TEAM

Development and pathologies of neuromuscular circuits

Group leader : F. Helmbacher

Research in our team aims to understand processes that control the development of neuromuscular circuits, and to uncover how alterations of these developmental processes lead to devastating neuromuscular pathologies in human.

FOR BEGINNERS

Research in our team aims to understand processes that control the development of neuromuscular circuits, and to uncover how alterations of these developmental processes lead to devastating neuromuscular pathologies in human.

We investigate the mechanisms that shape skeletal muscles and coordinate connectivity between spinal motor neurons and muscles, an essential process for the control of locomotion. Our current work focuses on the role of adhesion molecules controlling both neuronal connectivity and muscle shape, and owing to this work, have recently discovered the roots of a human myopathy: Facioscapulohumeral muscular dystrophy.

We tackle these questions by combining modern techniques of mouse genetics, imaging, bioinformatics and functional genomics, and have teamed up with human geneticists and pathologists, so as to design murine models of human neuromuscular pathologies such as FSHD.

FOR SPECIALISTS

Françoise Helmbacher Team studying development and pathologies of neuromuscular circuits at IBDM, IBDMLOne of the key questions in neurosciences is to understand the mechanisms involved in the assembly of complex circuitry. The big principles implied by this question are also found in circuits much simpler than brain circuits, and we have chosen to focus on the assembly of neuromuscular circuits for their relative simplicity. The organization of motor projections from motor neurons towards muscles is on one side stereotyped, based on the existence of a topographic link between the position of neurons in the spinal cord and that of their target muscles in the body. On the other side this organization is complex, since the multiplicity of tasks and movements the body is meant to execute is accompanied by a large functional and geographical diversity of muscles and neurons. Thus, understanding mechanisms that harmoniously orchestrate neuromuscular connectivity requires to integrate notions such as cell fate diversity (both on the neuronal and muscular side) and mutual dependency, and to focus on the identification of signals successively exchanged during development. We thus study the signals acting on specification, axonal guidance, muscle migration/morphogenesis, signals allowing numerical control of the size of each neuromuscular unit (muscle and corresponding motor pool, through regulation of neuronal survival or muscle growth), and finally signals integrating functional activity.

To understand how these circuits are connected and shaped, 1) we use genetic markers of subpopulations of motor neurons or muscles, 2) we try to identify signaling molecules exchanged by muscles and motor neurons and involved in the different phases of neuromuscular assembly, and 3) we use genetic methods to manipulate the functions of these molecules so as to determine the anatomical and functional consequences of these alterations.

1-     A major effort aim is to identify molecules involved in the assembly of neuromuscular connectivity. We focus in particular on signaling cues and their receptors, such as ephrins and Eph Receptors, such as neurotrophic factors and their tyrosine kinase receptors (HGF/Met; GDNF/Ret, etc), and more recently on adhesion molecules of the immunoglobulin superfamily, such as the FAT and DACHSOUS protocadherins.

2-     It is common for many of these signaling molecules to act simultaneously in neurons and in their targets, by eliciting distinct but complementary biological responses. For example HGF/Met signaling is required to controls both muscle migration and several aspects of motor neuron biology (axon guidance, specification, survival). Thus, to be able to distinguish their respective actions on the various cell types involved in the neuromuscular construction, we used advanced molecular genetics to ablate their functions in a tissue specific manner.

Françoise Helmbacher Team from IBDM studying development and pathologies of neuromuscular circuits 3-     Our recent studies on the role of the protocadherin FAT1 in muscular development have identified FAT1 for its key role in the pathophysiology of a human myopathy, facioscapulohumeral dystrophy (FSHD), a hereditary condition leading to regionalized muscle wasting (Caruso et al., PLOS Genetics, 2013). In brief, ous results suggest that a tissue-specific deregulation of FAT1, by perturbing is early role in muscle morphogenesis, has the potential to phenotype surprisingly identical to the most characteristic clinical symptoms of FSHD, including not only regionalized muscle wasting, but also vascular retinopathy. Our objectives are to define to which extent and in which cell type depletion of FAT1 (and the resulting signaling consequences) are likely to contribute to FSHD symptoms, thus identifying mechanistic nods that qualify as optimal therapeutic targets.

Ultimately, these studies will lead to developing therapeutic strategies applicable in patients with neuromuscular disorders, meant to bypass the consequences of a developmental mistake.


Selected publications

PUBLICATION

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis.

Helmbacher F.
PLoS Biol. 2018 May 16;16(5):e2004734. doi: 10.1371/journal.pbio.2004734. PMID: 29768404

PUBLICATION

Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells

Fabienne Lamballe, Sara Toscano, Filippo Conti, Maria Arechederra, Nathalie Baeza, Dominique Figarella-Branger, Françoise Helmbacher and Flavio Maina
Oncotarget. 2016 Oct 9. PMID: 27732969

PUBLICATION

Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis.

Fan Y, Richelme S, Avazeri E, Audebert S, Helmbacher F, Dono R, Maina F.
PLoS Genet. 2015 Sep 22;11(9):e1005533. doi: 10.1371/journal.pgen.1005533. eCollection 2015. PMID: 26393505

PUBLICATION

Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

Mariot V, Roche S, Hourdé C, Portilho D, Sacconi S, Puppo F, Duguez S, Rameau P, Caruso N, Delezoide AL, Desnuelle C, Bessières B, Collardeau S, Feasson L, Maisonobe T, Magdinier F, Helmbacher F, Butler-Browne G, Mouly V, Dumonceaux J.
Ann Neurol. 2015 Sep;78(3):387-400. doi: 10.1002/ana.24446. PMID: 26018399

PUBLICATION

Stromal Fat4 acts non-autonomously with Dchs1/2 to restrict the nephron progenitor pool.

Bagherie-Lachidan M, Reginensi A, Pan Q, Zaveri HP, Scott DA, Blencowe BJ, Helmbacher F, McNeill H.
Development. 2015 Aug 1;142(15):2564-73. doi: 10.1242/dev.122648 PMID: 26116661

PUBLICATION

Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype.

Puppo F, Dionnet E, Gaillard MC, Gaildrat P, Castro C, Vovan C, Bertaux K, Bernard R, Attarian S, Goto K, Nishino I, Hayashi Y, Magdinier F, Krahn M, Helmbacher F, Bartoli M, Lévy N.
Hum Mutat. 2015 Apr;36(4):443-53. doi: 10.1002/humu.22760. PMID: 25615407

PUBLICATION

Celsr3 is required in motor neurons to steer their axons in the hindlimb.

Chai G, Zhou L, Manto M, Helmbacher F, Clotman F, Goffinet AM, Tissir F.
Nat Neurosci. 2014 Sep;17(9):1171-9. doi: 10.1038/nn.3784. PMID: 25108913

PUBLICATION

Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons

Caruso N, Herberth B, Lamballe F, Arce-Gorvel V, Maina F, Helmbacher F.
BMC Biol. 2014 Aug 14;12(1):56. PMID: 25124859

PUBLICATION

Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy.

Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy N, Helmbacher F.
PLoS Genet. 2013 Jun;9(6):e1003550. PMID: 23785297

PUBLICATION

gdnf activates midline repulsion by Semaphorin3B via NCAM during commissural axon guidance.

Charoy C, Nawabi H, Reynaud F, Derrington E, Bozon M, Wright K, Falk J, Helmbacher F, Kindbeiter K, Castellani V.
Neuron. 2012 Sep 20;75(6):1051-66. PMID: 22998873

PUBLICATION

Pool-specific regulation of motor neuron survival by neurotrophic support.

Lamballe F, Genestine M, Caruso N, Arce V, Richelme S, Helmbacher F*, Maina F*. (* co-senior authors)
J Neurosci. 2011 Aug 3;31(31):11144-58. PMID: 21813676

PUBLICATION

Enhanced neuronal Met signalling levels in ALS mice delay disease onset.

Genestine M, Caricati E, Fico A, Richelme S, Hassani H, Sunyach C, Lamballe F, Panzica GC, Pettmann B, Helmbacher F, Raoul C, Maina F, Dono R.
Cell Death Dis. 2011 Mar 17;2:e130. PMID: 21412276

PUBLICATION

Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons.

Gascon E, Gaillard S, Malapert P, Liu Y, Rodat-Despoix L, Samokhvalov IM, Delmas P, Helmbacher F, Maina F, Moqrich A.
J Neurosci. 2010 Sep 15;30(37):12414-23. PMID: 20844136

PUBLICATION

Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb.

Kramer ER*, Knott L*, Su F, Dessaud E, Krull CE, Helmbacher F*, Klein R*. (*These authors contributed equally to the work).
Neuron. 2006 Apr 6;50(1):35-47. PMID: 16600854

PUBLICATION

Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools.

Helmbacher F, Dessaud E, Arber S, deLapeyrière O, Henderson CE, Klein R, Maina F.  
Neuron. 2003 Aug 28;39(5):767-77. PMID: 12948444

PUBLICATION

Coupling Met to specific pathways results in distinct developmental outcomes.

Maina F, Panté G, Helmbacher F, Andres R, Porthin A, Davies AM, Ponzetto C, Klein R.
Mol Cell. 2001 Jun;7(6):1293-306. PMID: 11430831

PUBLICATION

The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration.

Adams RH, Diella F, Hennig S, Helmbacher F, Deutsch U, Klein R.
Cell. 2001 Jan 12;104(1):57-69. PMID: 11163240

PUBLICATION

Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline.

Yokoyama N, Romero MI, Cowan CA, Galvan P, Helmbacher F, Charnay P, Parada LF, Henkemeyer M.
Neuron. 2001 Jan;29(1):85-97. PMID: 11182083

PUBLICATION

Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons.

Helmbacher F, Schneider-Maunoury S, Topilko P, Tiret L, Charnay P.
Development. 2000 Aug;127(15):3313-24. PMID: 10887087

Powerpoint support for nervous system development and pathologies classes – 2013 (in french)
Helmbacher M1 Devt-patho-Neuro 2013

Powerpoint support for cellular decision classes – 2013 (in french)
Helmbacher M1 Cellular Decision 2013

Interactions

IBDM
NATIONAL
  • Nicolas Levy, INSERM UMR910, La Timone, Marseille
  • Gillian Butler Browne, Institut de Myologie, Paris
INTERNATIONAL
  • Robin Fitzsimons, University of Sydney, Australia
  • Saverio Bellusci, University Justus Liebig, Giessen, Germany
  • Helen McNeill, Samuel Lunenfeld research Institute, Canada

Funding

FSHD funding for Françoise Helmbacher Team from IBDM, IBDML

FSH funding for Françoise Helmbacher Team from IBDM, IBDML

AFM funding for Françoise Helmbacher Team from IBDM, IBDML

Members more

  Dominique Fragano
Françoise Helmbacher
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Françoise Helmbacher

Researcher

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Pierre-antoine Ferracci

MSc student

Dominique Fragano
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Dominique Fragano

Technical staff

Overview

Animal model organism
Biological process studied
  • Neuromuscular development
  • Neurovascular development
Biological techniques
  • Mouse genetics (knockouts, cre-Lox, BAC transgenics)
  • Cell cultures
  • Bioinformatics
  • Functional genomics
Medical applications
  • Neuromuscular pathologies
  • Facioscapulohumeral dystrophy