PC12 VARIANTS WITH ALTERED ORNITHINE DECARBOXYLASE EXPRESSION PATTERNS EXHIBIT ALTERED SIGNAL-TRANSDUCTION CAPABILITIES

Nerve growth factor (NGF) induced differentiation of primary and perma nent neuronal cell cultures is accompanied by a rapid and transient in duction of ornithine decarboxylase (ODC) mRNA and enzymatic activity; a similar ODC induction accompanies mitogenic effecters in many additi onal cell types. In an effort to assess the role of ODC activity in ne uronal cell biology, we have used the ODC suicide substrate inhibitor difluoromethylornithine (DFMO) to select PC12 cell variants with alter ed ODC expression patterns and characterized the resulting phenotypes. The variants fall into three distinct classes based upon their patter ns of ODC mRNA and ODC activity levels; however, all are severely comp romised in their ability to respond properly to NGF treatment. Followi ng NGF treatment, none of the variants exhibits any morphological diff erentiation, In addition, none of the variants is capable of properly inducing either c-fos mRNA (an ''immediate early'' response) or GAP-43 mRNA (a ''late'' response) following NGF treatment. Our data suggest that altered ODC metabolism can lead to inactivation of element(s) act ive very early in the normal NGF signal transduction cascade. (C) 1995 Academic Press, Inc.