Our earlier work demonstrated that certain populations of brain neurons which do not synthesize catecholamine (CA) neurotransmitters in vivo, will, when grown in culture with muscle-derived differentiation factor (MDF), unexpectedly express the gene for the CA biosynthetic enzyme tyrosine hydroxylase (TH). In this paper, we sought to determine whether MDF could also regulate TH expression in those neurons which normally synthesize CA neurotransmitters. Incubation of cultured dopamine neurons from the ventral midbrain with MDF elevated the levels of TH mRNA and TH enzyme activity 5- to 40-fold higher than that measured in control cultures. Sympathetic neurons were unaffected by a similar MDF treatment. Unlike the 2-day critical period for MDF-responsivity in non-CA neurons. CA neurons remained susceptible to MDF's influence over an extended developmental interval (E14-18), suggesting that MDF may be important for TH gene regulation in brain CA neurons even differentiation is complete. Because of these unique properties, MDF may provide a unique opportunity to explore ways in which the TH gene might be directly manipulated in these cell populations in order to correct the CA imbalances that occur in certain neurological diseases and disorders.