TROPHIC ACTIONS OF TRANSFORMING GROWTH-FACTOR-ALPHA ON MESENCEPHALIC DOPAMINERGIC-NEURONS DEVELOPING IN CULTURE

Transforming growth factor alpha messenger RNA and protein levels are highest in the striatum, the target area of mesencephalic dopaminergic neurons of the substantia nigra, suggesting a role as a target-derive d neurotrophic factor for these cells. To test this hypothesis, we cha racterized the actions of transforming growth factor alpha on fetal ra t dopaminergic neurons in culture. Transforming growth factor alpha pr omoted dopamine uptake in a dose- and time-dependent manner. Administr ation of transforming growth factor alpha at the time of plating for 2 h produced a significant increase in dopamine uptake after five days of growth in vitro. As cultures aged they became less responsive to tr ansforming growth factor alpha, such that longer times of exposure wer e required to elicit a similar, but weaker, response. Dopaminergic cel l survival was selectively promoted by transforming growth factor alph a, since there was an increase in the number of tyrosine hydroxylase-i mmunostained cells without a parallel increase in the total number of neuron-specific enolase-immunopositive cells. Neurite length, branch n umber and soma area of tyrosine hydroxylase-immunopositive cells also were enhanced by transforming growth factor alpha treatment. Increases in each of the dopaminergic parameters due to transforming growth fac tor alpha were accompanied by a rise in glial cell number, making it p ossible that these effects were mediated by this cell population. The neurotrophin antagonist, K252b, failed to inhibit the transforming gro wth factor alpha-induced increase in dopamine uptake, indicating that transforming growth factor alpha's effects were not mediated by neurot rophin mechanisms. The actions of transforming growth factor a on the differentiation of dopaminergic neurons only partially overlapped with those of epidermal growth factor. Thus, while transforming growth fac tor a and epidermal growth factor are believed to share the same recep tor they differentially affect dopaminergic cell development in vitro. These results indicate that transforming growth factor alpha is a tro phic factor for mesencephalic cells in culture and suggests that trans forming growth factor alpha plays a physiological role in the developm ent of these cells in vivo.