Brockes and Kintner in 1986 defined five criteria for a substance to meet to be considered a neurotrophic factor:
1) Produced by nerves
2) Present in the blastema
3) Its level is decreased by denervation
4) It rescues cell cycling in a denervated blastema
5) Its specific removal with a blocking antibody mimics denervation
The current argument is over which neurotrophic factor is responsible for filling all five criteria. Claims have been made for transferrin, a protein that is normally present in periheral nerves. Studies have shown that it accumulates even higher during nerve regeneration, but more testing is needed to determine if it meets the last two criteria (8).
Mullen, et al., reported in 1996 evidence for Fibroblast Growth Factor (FGF). A small polypeptide, FGF restored the activity of the blastema in denerved limbs. The study also found FGF receptors present in the blastema (8, 14).
However, a recent study lead by L. Wang negated Mullen's findings and presented a strong argument for Glial Growth Factor (GGF). GGF belongs to the neuregulin growth factor family and is active on glial cells, including Schwann cells. Brockes and Kintner already showed GGF fulfilled the first four criteria to being a neurotrophic factor in 1986. The Wang 2000 study not only demonstrated that GGF fulfilled the fifth criteria, but showed again that it is capable of rescuing cell cycling. The researches refuted the claim of FGF as the neurotrophic factor by showing that the blastema expresses FGF genes by themselves, without the aid of the nerves. They suggest that an inhibitor system comes into play after deneravtion, meaning FGF would appear to rescue the cycling when in fact it is only overcoming the inhibition (17).
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