Development and plasticity of neural network

Our objective is to explore molecular and cellular mechanisms of development.

Our projects are developed on wild-type and genetically-manipulated mice: i) on the olfactory system characterized by the continuous production throughout life of sensory neurons in the olfactory epithelium and populations of interneurons in the olfactory bulb (OB), ii) on motor pathways 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 differentiation of olfactory sensory neurons, and in particular the role of odorant receptors and of their local synthesis in axons in the pathfinding of sensory neuron axons;
  • The role of the RNA-binding protein Fragile X Mental Retardation Protein (a key regulator of local translation of mRNAs in dendrites) and of of its target mRNA (i.e. the CamKIIa mRNA), in the functional integration of granule cells into the adult OB network;
  • The study of the molecular bases underlying the lateralization of motor control during development, and in particular the role in these processes of RAD51 (gene involved in DNA repair) whose mutations in human have been linked to congenital mirror movements.

-- Homotypic and heterotypic adhesion induced by odorant receptors and the b2-adrenergic receptor. (2013) PLoS One more

-- RAD51 haploinsufficiency causes congenital mirror movements in humans.(2012) Am J Hum Genet. more

-- Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb. (2011) J Neurosci more

Highlights

  • We demonstrated that odorant receptor (OR) mRNAs are associated to polysomes in olfactory axons, and that their axonal localization and translation is developmentally-regulated (Dubacq et al., 2009).
  • We showed, using a biophysical assay, that ORs, as well as the b2-adrenergic receptor (a non-OR GPCR known to recapitulate in vivo the functions of ORs in axon sorting) have the ability to mediate adhesion between cells (Richard et al., 2013).
  • We demonstrated, using RNA-interference in vivo, that FMRP plays a major role in the morphological differentiation and functional insertion of granule cells (GCs) into the adult OB network (Scotto-Lomassese et al., 2011).
  • We showed that the CaMKIIa mRNA is transported in GCs dendrites, and that its synaptic localization is enhanced by olfactory stimuli in an NMDA-dependent manner. In mice devoid of CaMKIIa 3'UTR, CaMKIIa mRNA dendritic localization and olfactory associative learning are dramatically impaired (Néant-Féry et al., 2012).
  • We showed that a gene involved in human congenital mirror movements, the RAD51 gene (known for its role in DNA repair) is critically expressed in mouse motor cortex and corticospinal tracts during development (Depienne et al., 2012).

Future directions

  • Project 1: Characterization of cis- and trans-acting factors involved in the axonal localization and local translation of odorant receptor mRNAs, characterization of the protein synthesis and trafficking machineries in olfactory axons, characterization and modeling of the dynamics of axon-axon interactions using biophysical approaches and the tools of statistics physics.
  • Project 2: Identification of other FMRP target mRNAs and their role in GC dendrites, characterization of the structural modifications of the olfactory circuit induced by olfactory learning in adult mice, and of their molecular correlates in terms of dendritic transport and local translation of mRNAs. Role of FMRP in the neurogenic niche of the adult subventricular zone.
  • Project 3: Determination of i) the function of RAD51 in the developing mouse CNS; ii) the molecular scenario controlling midline crossing by corticospinal and transcallosal axons; iii) the contribution of appropriate decussation of the CST and normal transcallosal connections to the lateralization of motor control.

Collaborations

  • Charles Greer (Yale Univ., New Haven).
  • Martin Zapotocky (Acad. Sci. Czech Rep. and Charles Univ., Prague)
  • Frédéric Pincet (ENS, Paris)
  •  Alexandre Favereau et Marc Landry (Univ. Bordeaux 2)
  • Anne Didier (Univ. Lyon 1)
  • Armen Saghatelyan (Univ. Laval, Québec, Canada)
  •  Emmanuel Flamand-Roze (ICM, Paris)
  • Alain Chédotal (Institut de la Vision, Paris)