The addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to defined growth medium stimulated an intense neurite outgrowth from chick sensory ganglia explants. The development of radial neurites was concentration dependent. At low concentrations of TPA (1.6 to 16 nm), neurites were long but moderate in numbers. At higher concentrations (160 to 480 nm), TPA produced dense, short neurites that formed thick fascicles. This reduced outgrowth in length was not related to cytotoxicity and was found to be reversible when the tumor-promoting agent was removed. Neurite outgrowth was also accompanied by an increase in proliferation of nonneuronal cells. Blocking the proliferation of nonneuronal components by the mitotic inhibitor 1-β-d-arabinofuranosylcytosine did not inhibit neurite outgrowth, suggesting that the TPA-induced neurite differentiation was independent of nonneuronal cells. When TPA was tested in the presence of nerve growth factor, the induction of neurite differentiation was not affected. Other active tumor promoters including phorbol-12,13-didecanoate and mezerein also elicited neurite outgrowth, while nonpromoting agents such as phorbol and 4α-phorbol-12,13-didecanoate were ineffective.

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This work was supported in part by a grant from the National Osteopathic Foundation (L. Hsu) and Grants CA 32485 and CA 33212 from the National Cancer Institute (J. D. Laskin).

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