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Volume 17, Number 6, Issue of March 15, 1997 pp. 1950-1958
Copyright ©1997 Society for Neuroscience

Post-Transcriptional Regulation of the GAP-43 Gene by Specific Sequences in the 3 Untranslated Region of the mRNA

Received Oct. 31, 1996; revised Dec. 23, 1996; accepted Jan. 13, 1997.

Kao-Chung Tsai¹, Victor V. Cansino¹, Douglas T. Kohn¹, Rachael L. Neve², and Nora I. Perrone-Bizzozero¹

¹ Departments of Biochemistry and Neuroscience and Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, and ² McLean Hospital, Departments of Psychiatry and Genetics, Harvard Medical School, Boston, Massachusetts 02115

We have shown previously that GAP-43 gene expression during neuronal differentiation is controlled by selective changes in mRNA stability. This process was found to depend on highly conserved sequences in the 3 untranslated region (3 UTR) of the mRNA. To map the sequences in the GAP-43 3 UTR that mediate this post-transcriptional event, we generated specific 3 UTR deletion mutants and chimeras with the -globin gene and measured their half-lives in transfected PC12 cells. Our results indicate that there are two distinct instability-conferring elements localized at the 5 and 3 ends of the GAP-43 3 UTR. Of these destabilizing elements, only the one at the 3 end is required for the stabilization of the mRNA in response to treatment with the phorbol ester TPA. This 3 UTR element consists of highly conserved uridine-rich sequences and contains specific recognition sites for two neural-specific GAP-43 mRNA-binding proteins. Analysis of the levels of mRNA and protein derived from various 3 UTR deletion mutants indicated that all mutants were translated effectively and that differences in gene expression in response to TPA were attributable to changes in GAP-43 mRNA stability. In addition, the phorbol ester was found to affect the binding of specific RNA-binding proteins to the 3 UTR of the GAP-43 mRNA. Given that, like the GAP-43 mRNA, its degradation machinery and the GAP-43 mRNA-binding proteins are expressed primarily in neural cells, we propose that these factors may be involved in the post-transcriptional regulation of GAP-43 gene expression during neuronal differentiation.

Key words: GAP-43; post-transcriptional regulation; gene expression; neuronal differentiation; mRNA stability; RNA-binding proteins; PC12 cells

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