Expression of the gene encoding tyrosine hydroxylase (TH), the initial and rate-limiting enzyme of catecholamine biosynthesis, is regulated at the transcriptional level during neuronal development and in response to a variety of environmental stimuli. Nur-related factor 1 (Nurr1), a member of the orphan nuclear receptor superfamily, is required for development of dopamine-producing neurons in the ventral midbrain and for expression of TH in these neurons. In the present study, we found a direct activation of the rat TH gene promoter by Nurr1 in cultured cell lines. This activation appeared to be dependent on multiple regulatory elements conferring Nurr1 responsiveness to the promoter. We identified a Nurr1 response element (TH-NBRE1) in the proximal region of the TH promoter that mediates a moderate activation of the promoter. The sequence of TH-NBRE1 was highly homologous to that of the typical NGFI-B response element. Our findings suggest that Nurr1 may be implicated in the transcriptional control of TH gene expression during development or in response to altered physiological states.
Copyright 2000 Academic Press.