|dc.description.abstract||Close interaction between oligodendrocytes and axons is essential to initiate
myelination and to form specialised domains along myelinated fibres. These domains
are characterised by the assembly of protein complexes at the axon-glia interface and
key components of these complexes are the Neurofascins.
Neurofascins are transmembrane glycoproteins belonging to the L1 subgroup of the
Immunoglobulin (Ig) superfamily of cell adhesion molecules. The Neurofascin (Nfasc)
gene is subject to extensive alternative splicing. Two of the best characterised isoforms
are Nfasc155 and Nfasc186, which are expressed in glia and neurons respectively. In
myelinated fibres, Nfasc186 is the predominant isoform expressed at nodes of Ranvier
and axon initial segments (AIS) in both the central and peripheral nervous system (CNS
and PNS), whereas Nfasc155 resides on the glial side of the paranodal axoglial junction.
The Neurofascin gene has been inactivated by homologous recombination and
Neurofascin-null mice die within the first week of postnatal life. The main focus of this
work was to investigate the role of the Neurofascins in the developing CNS.
Similarly to what has been previously observed in the PNS, this study shows that in
myelinated fibres of the spinal cord, nodal and paranodal markers are mislocalised and
axoglial junctions do not form in the absence of the Neurofascins. In contrast to the
PNS, where ensheathment of axons is unaffected, myelin proteins in the CNS are
greatly reduced in the mutant. This appears to be due to the reduced ability of
oligodendrocyte myelinating processes to extend along axons.
This work also shows that the role of Nfasc186 is to maintain the long term stability
of the AIS rather than its assembly.
In the PNS, Nfasc186 was found to play an essential role in node assembly. However,
PNS and CNS nodes are likely to assemble by different mechanisms. To investigate the
relative contribution of the Neurofascin isoforms in CNS node assembly, this work
made use of transgenic lines in which either neuronal Nfasc186 or glial Nfasc155 was
expressed on a Neurofascin null background. Expression of either isoform was found to
independently rescue the nodal complex and a model of how the Neurofascins
cooperate in the assembly of the CNS node of Ranvier is proposed.||en