Neuromuscular Development

The original focus of the team was essentially related to the aspect of neural diversification among motor neurons, and the developmental mechanisms underlying this diversification, as well as the consequent topographical organization of motor projections towards the muscle targets

Motor neuron specification

Each class of MNs can be recognized not only by its position and the position of its target muscle in the periphery, but also by their molecular characteristics. These are encoded through the expression of selective combinations of transcription factors, each of which controls the expression of a number of downstream effectors, among which axon guidance receptors. Classical studies by experimental biologists had established that Motor neurons become progressively specified to carry the intrinsic knowledge of their anatomical and molecular specificity. Acquisition of such characteristics is specified in nascent motor neurons by environmental signals. One of our long standing interest is to understand the mechanisms governing acquisition of motor neuron cell fates, and in particular in exploring those specified by interaction with peripheral structures.

Selected Publications

  • Helmbacher F. Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis. PLOS Biology (2018) 16(5) e2004734 | PMID: 29768404 | doi: 10.1371/journal.pbio.2004734 | previously posted as preprint: |
  • 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 | doi:10.1186/s12915-014-0056-6 |
  • Helmbacher F, Dessaud E, Arber S, Delapeyriere O, Henderson CE, Klein R and Maina F. Met Signaling Is Required for Recruitment of Motor Neurons to PEA3-Positive Motor Pools. Neuron (2003) 39, 767-77. | PMID: 12948444 | doi: 10.1016/S0896-6273(03)00493-8 |

Motor Axon Guidance

Establishment of the topographic innervation of limb muscles by motor neurons involves as series of binary decision between two alternative axonal trajectories, during which growth cones of each motor neuron subtype evaluate peripheral signals and chose their appropriate trajectory to reach their specific muscle target.

This has long been my favorite topic after the initial discovery that the EphA4 tyrosine kinase receptor played an essential role in motor axon pathway selection in the limb (Helmbacher et al., 2000), and that this particular guidance decision represented an excellent model system to study.

Control of Dorso-ventral pathway selection by limb-innervating Motor axons: Schematic model representing a cross section of a mouse embryo at around E11.5, representing limb-innervating motor neurons in the spinal cord, and the peripheral trajectories of their axons, with some of the molecular players involved. LMCl axons (green) project to the dorsal part of the limb bud. This dorsal trajectory is ensured by the combinatorial activities of several overlapping systems, including EphrinAs/EphA4, GDNF/Ret/Gfra1, and more recently Celsr3/Fzd3. Ventral trajectory of LMC(m) axons is governed by ephrinBs/EphBs and Sema/Npn signaling.

Selected Publications

  • 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. Nat. Neuroscience (2014) Aug 10. | PMID: 25108913 | doi:10.1038/nn.3784.
  • Charoy C, Nawabi H, Reynaud F, Derrington E, Bozon M, Wright K, Falk J, Helmbacher F, Kindbeiter K, Castellani V. gdnf Activates Midline Repulsion by Semaphorin3B via NCAM during Commissural Axon Guidance. Neuron. (2012) Sep 20;75(6) | PMID: 22998873 |
  • Kramer E*, Knott L*, Su F, Dessaud E, Krull CE, Helmbacher F*, and Klein R*. Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor axon pathway selection in the limb. Neuron (2006). April 6, 50(1):35-47. | PMID: 16600854 | doi: 10.1016/j.neuron.2006.02.020 | (*equal contributions).
  • Helmbacher, F, Schneider-Maunoury, S, Topilko, P, Tiret, L and Charnay, P. Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development (2000) 127, 3313-24. | PMID : 10887087 |