Development and plasticity of neural network

Our objective is to explore original molecular and cellular mechanisms of normal and pathological development and plasticity of neural networks.

Our work is carried out in wild-type and genetically-manipulated mice and zebra fish, on:

i) the olfactory system characterized by continuous double neurogenesis producing sensory neurons in the olfactory epithelium and interneurons in the olfactory bulb;

ii) the motor system involved in the lateralization of motor control (i.e. the ability to perform independent movements with the two hands).

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We focus our projects on three main questions:

  • The study of the development and guidance of olfactory sensory axons, and in particular the role of odorant receptors and of their local synthesis in axons in the pathfinding of sensory neuron axons (animal model: mouse), as well as the role of mechanical tension of axons in their fasciculation/defasciculation (animal models: mouse and zebrafish);
  • The role of the RNA-binding protein Fragile X Mental Retardation Protein (a key regulator of local translation of mRNAs in dendrites), andof the primary cilium and cAMP signalling, in the migration and functional integration of granule cells into the olfactory bulb network;
  • The study of the cellular and molecular bases underlying the midline crossing of the corticospinal tract and the lateralization of motor control: new insights from the congenital mirror movement paradigm.

Highlights

  • We have shown that:
  • the mechanical tension of the olfactory axons regulates their fasciculation, and that this fasciculation is the result of a competition between axonal tension and adhesion (Smit et al., 2017);

  • FMRP and dendritic translation of CaMKIIa mRNA are required for the structural plasticity of granular cells, itself necessary for olfactory learning (Daroles et al., 2016);

  • CamKIIa expression defines two distinct subpopulations of granular cells involved in different types of olfactory learning (Malvaut et al., 2017) ;

  • DCC controls the crossing of the median line by the corticospinal tract in a non-cell-autonomous manner (Welniarz et al., 2017);

  • Mutations in the Netrin gene are responsible for the syndrome of mirror movements (Méneret et al., 2017).

Future directions

  • Projet 1: Characterization of cis- and trans-acting regulators of the axonal localization and translation of mRNAs encoding mouse olfactory receptors, characterization of protein synthesis machinery and trafficking in olfactory axons; characterization of the olfactory axon interactions in vivo in mice (Coll. M. Trichet, Array Tomography) and zebrafish, and of the role of mechanical forces in development/guidance of these axons (Coll. M. Bréau, IBPS).

  • Projet 2: Characterization of the role of the primary cilium and cAMP signalling in the migration and functional insertion of the granular cells of the olfactory bulb of the mouse. Study of the defects induced by the absence of FMRP.

  • Projet 3: Momic or the Congenital Mirror Movements (CMM) paradigm: The three genes known to be involved in this disease are DCC, NTN1 and RAD51. We have shown that MMC patients with a mutation in one of these three genes have an increased proportion of uncrossed corticospinal tract projections. Our hypothesis is that disruption of cortico-spinal axon crossing during development results in bilateral transmission of motor control. To test this hypothesis, we pursue 3 objectives: 1) to clarify the link between the crossing of the midline by the corticospinal tract and the lateralization of the motor control, 2) to elucidate the molecular scenario governing the guidance of the corticospinal tract during development, 3) to discover the cytoplasmic function of RAD51 in the cortico-spinal axons.

Collaborations

  • Bardoni Barbara (IMCP, Nice)
  • Bréau Marie (LBD et LJP, IBPS, Paris)
  • Chédotal Alain (Institut de la Vision, Paris)
  • Didier Anne (Univ. Lyon 1)
  • Flamand-Roze Emmanuel (ICM, Paris)
  • Greer Charles (Yale Univ., New Haven)
  • Métin Christine (Institut Fer à Moulin, Paris)
  • Saghatelyan Armen (Univ. Laval, Québec, Canada)
  • Schneider-Maunoury Sylvie (LBD, IBPS, Paris)
  • Spassky Nathalie (ENS, Paris)
  • Trichet Michaël (Electron Microscopy Plateform, IBPS)

  • Pierre Vincent (B2A, IBPS, Paris)

  • Zapotocky Martin (Acad. Sci. Czech Rep. and Charles Univ., Prague)