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The role of axonal cell adhesion molecules in optic nerve regeneration

Objective

To compare TAG-1 expression after optic nerve injury in fish and rodents.
To ablate TAG-1 function in fish retinal ganglion cells (RGCs) using antibody and inhibitory protein reagents.
To introduce TAG-1 function into regenerating rodent RGCs using transgenic techniques, hormonal induction and injection of purified protein.
Use reporter gene constructs in transgenic mice and fish to identify key regulatory elements involved in TAG-1 and F3 expression in RGCs before and after injury.
Use sequence analysis, in vitro footprinting techniques and site-directed mutagenesis to identify transcription factor binding sites within the relevant regulatory elements.
Use comparisons between fish and rodents to investigate the expression of F3 and other potential candidate axCAMS.

The peripheral nervous system (PNS) of mammals, and the central nervous system (CNS) of some "lower" vertebrate species, are capable of regeneration. In contrast, the CNS of mammals shows particularly poor regenerative capacity. We will look after CNS injury, in rodents and fish, at the expression of a set of axonal cell adhesion molecules (axCAMs) known to be expressed during embryonic axonogenesis. Regeneration after injury may depend on the ability of the injured neuron to re-express specific embryonic axCAMs. We will exploit the different regenerative capacities of fish versus rodents to identify axCAMs differentially expressed in these species during regeneration. Such molecules are likely to play a role in whether or not axons will regenerate. The major goal of this proposal is to understand the regulation of such axCAMs in response to axon injury, with the objective of manipulating their expression to test whether they contribute to regenerative capacity.
Recent results reveal a marked lack of re-expression of TAG-1, an immunoglobulin-like molecule, in retinal ganglion cells after optic nerve injury in rats. Since TAG-1 has been implicated in the axonal outgrowth of embryonic neurons it is conceivable that the absence of TAG-1 is a significant factor in the inability of adult CNS neurons to regenerate. In support of this, TAG-1 is re-expressed by cultured adult rat PNS sensory neurons, known to have regenerative capability.
Thus, a substantial part of this proposal aims to 1) test whether lack of TAG-1 expression after optic nerve injury does contribute to the failure of retinal ganglion cells to regenerate and 2) understand how the expression of TAG-1 is regulated during nerve injury. We further aim to test the role of TAG-1-related molecules, in particular F3, whose properties suggest that it may mediate signals that inhibit RGC regeneration.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

University of Sheffield
Address
Western Bank
S10 2UH Sheffield
United Kingdom

Participants (4)

Consejo Superior de Investigaciones Científicas
Spain
Address
4,Calle Arturo Duperier
28029 Madrid
Università degli Studi di Bari
Italy
Address
Piazza Giulio Cesare 1
70124 Bari
Universität Konstanz
Germany
Address
10,Universitätsstrasse
78434 Konstanz
Universität Zürich
Switzerland
Address
190,Winterthurerstrasse
8057 Zurich