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Ed. Note: The following
is a press release from the American Society For Cell Biology (ACSB)
December 2, 2004
Our able-bodied lives hang by a thread. Severed axons
do not regenerate following damage to the brain or the spinal cord,
because their regrowth is blocked in part by a glial scar that forms a
barrier both physical and chemical. To bridge that glial scar, the
Pharmacology laboratory of Sally Meiners at the UMDNJ-Robert Wood Johnson
Medical School in New Jersey is designing grafts or scaffolds that
incorporate small molecules from the extracellular matrix (ECM) to coax
axons back across the gap and onto fertile ground for regrowth.
Here Meiners reports preliminary success with one such
molecule, a 15 amino acid peptide called C3 found in human tenascin-C (a
type of protein known as “fnC”). Interestingly, tenascin-C is an ECM
protein that helps “wire up” the developing central nervous system (CNS)
early in life. In Meiners’s experiments, the C3 peptide gave directional
clues to the growing ends (‘neurites’) of rat neurons cultured in dishes.
Given a choice, neurites preferentially crossed onto substrates coated
with C3, a process she defines as “neurite attraction.” Intriguingly,
neurites crossed onto C3 even in the presence of chondroitin sulfate
proteoglycans, a major class of inhibitory molecules present in glial
scars. Thus, adding C3 to grafts might help regrowing axons enter scar
tissue in brain or spinal cord lesions.
However, the C3 peptide also had an undesirable trait:
the neurites growing on C3 substrates did not want to leave. This was bad
news for potential CNS grafts, since axons must not only enter the graft
at the near end of the lesion, they must also exit the graft at the far
end to reach their targets. To see if she could ‘fine tune’ C3’s activity,
Meiners modified its amino acid sequence. She came up with three synthetic
versions: one that attracted and retained neurites, a second version that
retained but did not attract them, and a third that attracted but did not
retain them.
“Since the ‘exit phase’ is a major concern with CNS
grafts,” says Meiners, “these results suggest it will be possible to
design grafts in which ‘attractive’ fnC-derived peptides with minimal
retention activity entice axons to migrate across the glial scar. This
would facilitate guided axonal regrowth following CNS injury.” She
acknowledges that this in vitro work is still a long way from actually
regrowing severed axons in CNS patients. To bridge this gap, her
laboratory is now testing these ideas in an in vivo model of spinal cord
injury.
Neurite Attraction and Neurite Retention are Mediated
by Distinct Sites in the FnC Domain of Human Tenascin, -C H. Liu, 1 M.
Schachner, 2 S. A. Meiners1; 1 Pharmacology, UMDNJ-Robert Wood Johnson
Medical School, Piscataway, NJ, 2 Zentrum fur Molekulare Neurobiologie,
Universitaet Hamburg, Hamburg, Germany
At the ASCB Meeting: Session 174, Minisymposium 5: ECM
Biogenesis & Function, Room 147A/B. Author presents: Sunday, Dec. 5, 3:40
— 5:45 PM.
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