research / Overview

We study the development and pathologies of neuromuscular circuits in vertebrates. Our work combines the advantages of mouse and chick models to study the topographical assembly of selective neuromuscular circuits by focusing on subpopulations of motor neurons and their respective target muscles. We have long been focusing on mechanisms of motor axon guidance, motor neuron specification and pool specific control of motor neuron survival. More recently we also started to explore the relevance of these developmental mechanisms for the study of neuromuscular pathologies.

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

One 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.

Three recent publications:

- Caruso N., Herberth B., Lamballe F., Arce-Gorvel V., Maina F., and Helmbacher F. Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons. BMC Biology 2014, 12:56 | PMID:25124859 | (more...)
- F. Lamballe, M. Genestine, N. Caruso, V. Arce, S. Richelme, F. Helmbacher*, F. Maina*. (2011). Pool-specific regulation of motor neuron survival by neurotrophic support. J. Neurosci. 2011, Aug 3;31(31):11144-58. PMID:21813676. (*co-last and co-corresponding authors). (more...)
- Chai G, Zhou L, Manto M, Helmbacher F, Clotman F, Goffinet AM, Tissir F. Celsr3 is required in motor neurons to steer their axons in the hindlimb. (2014) Nature Neuroscience (2014), Aug 10. | PMID: 25108913 | (more...).

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.

Recent publication:

- 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. and Helmbacher F. (2013). Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of Facioscapulohumeral dystrophy. PLoS Genet 9(6): e1003550. doi:10.1371/journal.pgen.1003550. (more...)

- 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, and Levy, N. (2015). Identification of variants in the 4q35 gene FAT1 in patients with a Facioscapulohumeral dystrophy (FSHD)-like phenotype. Human Mutation, 2015, 23 JAN. DOI: 10.1002/humu.22760 | PMID 25615407 |

- Mariot V, Roche S, Hourdé C, Portilho D, Sacconi S, Puppo F, Rameau P, Caruso N, Delezoide AL, Desnuelle C, Bessières B, Collardeau S, Feasson L, Maisonobe T, Magdinier F, Helmbacher F., Mouly V, Butler-Browne G. Dumonceaux J. Correlation between low FAT1 expression and early affected muscle in FSHD. Annals of Neurology, 2015, MAY 28. DOI: 10.1002/ana.24446 | PMID: 26018399 |

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

Annual lectures on Neuronal specification in the spinal cord and motor neuron specification (in french, for Master students):

Page Cours M1

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last updated 28.06.2015