Development of the spinal cord organization

The development of the central nervous system is a complex event that depends both upon genetic and environmental factors and involves interactions between neuronal and non-neuronal cells (neural interaction). Altogether these interactions orchestrate the genesis of distinct but coordinated neuronal assemblies able to generate fine-tuned behaviors. 

The general aim of our research team is to better understand the mechanisms leading to the formation of the first functional neuronal networks during embryonic development of the CNS by using the mouse and the chicken embryonic spinal cords as models.

Our research project is oriented along two axis:

  • Along the first axis, the aim of our project is to characterize the nature and the evolution of early neuronal interactions at the onset of synaptogenesis by analyzing the spontaneous electrical activity of the emerging neuronal spinal cord networks.
  • Along the second axis we aim at determining how the first functional neuronal networks influence and are influenced by microglia and oligodendrocyte progenitor cells.

Glycine release from radial cells modulates the spontaneous activity and its propagation during early spinal cord development J Neurosci. 2010.

Microglia proliferation is controlled by P2X7 receptors in a pannexin-1-independent manner during early embryonic spinal cord invasion. J Neurosci. 2012.

Experience-dependent thalamocortical innervation regulates proliferation and distribution of NG2-expressing progenitors in the developing barrel cortex. Nature Neurosci. 2012.

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The general aim of our project is to better understand the mechanisms leading to the formation of the first functional neural spinal cord (SC) networks during embryonic development. This project is related to a fast-growing field of investigation aiming at understanding the role of neuron-neuron and of neuron-glia interactions in the emergence of specific neural assemblies able to generate fine-tuned behaviors. Although extensive research worldwide aims at understanding how functional neural networks develop, the mechanisms underlying the early electrical activity of the first neuronal assemblies remains ill-defined. Moreover most research has been focused on neuronal interactions, leaving the role of early glial cells (radial glial cells, microglia, NG2 cells) to be determined.

We are currently developing three specific projects:

The 1st project explore whether specific subpopulations of interneurons participate to the patterning of early spontaneous electrical activity at the onset of synaptogenesis in the embryonic SC.

Our 2nd project determines the role of neuron-microglia interactions during the generation of motor networks in the mouse embryonic SC.

Our 3rd project explores the nature and role of neuron-oligodendrocyte progenitors (NG2 cells) interactions during the generation of motor networks in the mouse embryonic SC. 

Highlights

We discovered that the progenitors radial cells regulate the activity of the developing SC neuronal network by releasing glycine. We obtained evidence that the cholinergic dependency of early SC activity reflects a presynaptic facilitation of GABA and glutamate synaptic release via nicotinic AChRs. Our study demonstrates that even in its earliest form, the activity of spinal MNs relies on a refined poly-synaptic network and involves a tight presynaptic cholinergic regulation of both GABAergic and glutamatergic inputs.

We also discovered that the beginning of the invasion of the embryonic SC by microglial cells takes place at the onset of synaptogenesis in the embryonic SC. During this period microglia already interact with neurons. Microglia play an active role by phagocyting apoptotic debris at the onset of motoneuron developmental cell death, while neurons control microglia proliferation through the activation of the purinergic receptor P2X7.

 We also found that NG2 cells received glutamatergic synapses from thalamocortical somatosensory axons and preferentially accumulated at the boundaries separating the cortical barrels processing the sensory information from distinct whiskers.

Future directions

We are currently developing three complementary projects.

  • The first project aims at exploring how the activity of the first functional SC interneurons (INs) is controlled by synaptic inputs and whether specific subpopulations of INs participate to the patterning of early spontaneous electrical activity at the onset of synaptogenesis in the embryonic spinal cord.
  • The second project aims at determining how microglia can regulate early developmental cell death of motoneurons (MNs) and of sensory neurons and if they regulate the early synaptogenesis on MNs in the embryonic spinal cord. In this project we will focus our attention on growth factors produced by microglia.
  •  The third project has for objective to determine if NG2 cells and their precursor cells the radial cells receive functional synaptic input at the onset of the synaptogenesis and to elucidate the function of these neuron-glial cells interactions the generation of spinal motor networks in the mouse and the chicken embryonic SC.

To address these issues, we are using genetic tools as for example the Cre/lox system, transgenic mice expressing eGFP to visualize cells, electrophysiology, optogenetic, immunohistochemistry, etc.

Collaborations

  • National:

-P. Branchereau, Bordeaux. (early SC electrical activity)

-M. Mallat, ICM, Paris. (Microglia)

-I. Couillin, UMR-IEM 6218, Orléans. (P2X7Rs)

-C. Wyart, ICM, Paris. (Optogenetic)

  • International:

-J. Meier, Berlin, Germany. (GlyRs)

-F. Alvarez, Atlanta, USA. (Early Renshaw cells)

-J.M. Rigo, Hasselt, Belgium. (GlyRs, radial cells, microglia)

-C. Francius and F. Clotman, Bruxelles, Belgium. (GABAergic INs)

-D. Riethmacher, Southampton, UK. (floxROSAfloxDTA mouse line)

-V. Gallo, Washington, USA. (OPC)

-D. Bergles, Baltimore, USA. (OPC, Gcamp, calcium imaging)

  • Local

-NPGS: S. El Mestikawy

-GOA: C. Betancur

-Plateforms (Imaging): S. Bolte