Date of Award

1996

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Dr. Susan Hockfield

Abstract

Unlike mammals, lower vertebrates are able to regenerate injured pathways of the central nervous system throughout life. The factors responsible for initiating this process are unknown. We have shown that in dissociated cell culture, goldfish retinal ganglion cells regenerate their axons in response to two factors derived from goldfish optic nerve glia. Axogenesis factor 1 (AF-1) is a small, hydrophilic peptide (700-900 daltons) that is inactivated by treatment with proteinase K, but heat-stable. A second factor, AF-2, is a basic polypeptide of c. 12kDa. Dissociated retinal cells remain viable in serum-free defined media for at least a week, but show little outgrowth. The addition of AF-1 induced up to 25% of cells in culture to extend processes > 75μm in length by 6 days; AF-2 had a lesser but highly significant effect. Retrograde tracing studies confirmed that neurite outgrowth was from retinal ganglion cells per se. The effects of AF-1 and AF-2 were not secondary to enhanced viability, since neither overall cell survival nor the number of retinal ganglion cells was affected by the presence of these factors. The activity of AF-1 and AF-2 was not mimicked by several defined factors tested over a broad concentration range, e.g., NGF, BDNF, NT-3, NT-4/5, CNTF, aFGF, bFGF, taurine and retinoic acid. The concentration of AF-1 is considerably higher in conditioned medium than in optic nerve homogenates, suggesting that it is actively secreted; AF-2 has a similar concentration intra-and extracellularly. Insofar as AF-1 and AF-2 derive from cells of the optic nerve and act upon retinal ganglion cells, they are likely to be important in inducing optic nerve regeneration in vivo.

Comments

This is an Open Access Thesis.

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