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Adhesion molecules in mammalian neural development and regeneration

Objective

Our objectives were - to characterize the structure, the function and the regulation of expression of adhesion molecules and - pinpoint their involvement in the ontogeny and regenerative processes of the mammalian nervous system.
PSA-NCAM, a unique permissive element for cell plasticity is involved in cell migration and required for activity-induced synaptic plasticity. Mechanisms controlling its expression have been discovered. Cell surface expression of adhesion molecules is under the control of neuronal activity, this observation provides a new framework for understanding activity-dependent reorganisation of synaptic networks. Growth factors up-regulate the expression of adhesion molecules in cultured Schawnn cells. Cell surface metallo-proteases play a role in peripheral nerve development and regeneration after injury. Activation of glycosyl-phosphatidylinositol anchored neuronal adhesion molecules leads to triggering of intracellular second messenger pathways. Effects of inhibitory molecules on axonal regeneration of CNS and PNS neurons depends on their developmental stage.
MAJOR SCIENTIFIC BREAKTROUGHS:
Laboratory 1 has chosen to work on the NCAM and F3 adhesion molecules of the immunoglobulin super-family which are known to play a role in axonal growth during development. Together with laboratory 4 they have shown, using post-hypophysial tissue explants as a model, that PSA-NCAM is necessary for the migration of oligodendrocyte progenitor cells, a population of cells particularly motile in vivo, and that PSA expression is controlled by NMDA receptor activation. They have also shown that PSA-NCAM is required for activity-induced synaptic plasticity and that it can be externalized on the cell surface of neurons by regulated exocytosis. Laboratory 2, in collaboration with laboratory 3, has shown that endopeptidase-24.11 is normally present at high levels in all neonatal and early postnatal Schwann cells and is gradually suppressed while myelinisation proceeds. This enzyme is re-expressed with the same time-course as NGF receptors after axotomy suggesting it might play a role in axonal regeneration. Laboratory 3 has mainly focused on the characterization and fate of Schwann cell precursors. It has also investigated the expression of molecules characterized by laboratories 1 and 2 on these precursors. The BM88 molecule recently cloned by laboratory 2 is expressed on both precursors and Schwann cells, so it will not be possible to consider it, as previously hoped, as a marker for the transition of the precursors to Schwann cells. Laboratories 1 and 2 have started a collaboration to investigate the possibility of using cerebellar tissue explants for retroviral infections aimed at testing the in vivo function of adhesion molecules. Laboratories 5 and 1 showed, using transfected cells as a model, that mimicking F3 triggering by cross-linking with antibodies induced the phosphorylation of intracellular substrates. In addition, they were able to co-immunoprecipitate a tyrosine kinase activity associated with F3 both in aggregated transfected cells and cerebellar neurons, reinforcing the observation that tyrosine kinases are involved in signalling following F3-mediated adhesion. Laboratory 6 has carried out experiments to decipher the function of the P31 (mCD24) adhesion molecule. Using P31 expressing glial cells, engineered by laboratory 1, it has shown that such cells used as a substrate monolayer prevented neurite regeneration of postnatal and adult sensory neurons and retinal ganglion cells but not neurite outgrowth of embryonic neurons. Neurons from a P31 knock-out mouse were also used. Taken together the data indicate that mature neurons expressed a receptor for P31 whose activation leads to inhibition of axonal growth.

Funding Scheme

CON - Coordination of research actions

Coordinator

Université d'Aix-Marseille II
Address
70 Route Léon Lachamp
13288 Marseille
France

Participants (5)

Consiglio Nazionale delle Ricerche (CNR)
Italy
Address
Via Archirafi 20
90123 Palermo
HELLENIC PASTEUR INSTITUTE
Greece
Address
Vassilissis Sofias Avenue 127
11521 Athens
UNIVERSITE DE GENEVE
Switzerland
Address
Place De L'universite 3
1211 Geneve 4
UNIVERSITY COLLEGE LONDON
United Kingdom
Address
Gower Street
London
United Medical and Dental Schools of Guy's and St.Thomas's Hospitals
United Kingdom
Address
Lambeth Palace Road
SE1 7EH London