PC12 variants with altered ornithine decarboxylase expression patterns exhibit altered signal transduction capabilities

Abstract

Nerve growth factor (NGF) induced differentiation of primary and permanent neuronal cell cultures is accompanied by a rapid and transient induction of ornithine decarboxylase (ODC) mRNA and enzymatic activity; a similar ODC induction accompanies mitogenic effectors in many additional cell types. In an effort to assess the role of ODC activity in neuronal cell biology, we have used the ODC suicide substrate inhibitor difluoromethylornithine (DFMO) to select PC12 cell variants with altered ODC expression patterns and characterized the resulting phenotypes. The variants fall into three distinct classes based upon their patterns of ODC mRNA and ODC activity levels; however, all are severely compromised in their ability to respond properly to NGF treatment. Following NGF treatment, none of the variants exhibits any morphological differentiation. 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) active very early in the normal NGF signal transduction cascade.