GROWTH FACTOR-INDUCED C-FOS EXPRESSION DEFINES DISTINCT SUBSETS OF MIDBRAIN DOPAMINERGIC-NEURONS

Growth factors are considered pivotal for the development, maintenance , and function of mesencephalic dopaminergic neurons. Recent studies h ave identified a plethora of growth factors which support the survival and differentiation of embryonic dopaminergic neurons. However, the e xact cellular targets of these growth factors, and, thus, their precis e mechanisms of action, remain largely unknown. To identify these cell ular targets, we analysed, at the single cell level, growth factor-ind uced c-fos expression in dissociated mesencephalic cell cultures deriv ed from a fos-lacZ transgenic mouse line. Pharmacological interference with cell-cell communication was utilized to control for direct growt h factor effects. beta-Galactosidase-expressing cells were phenotypica lly characterized by immunocytochemistry to specific neural cell marke rs. Glia cell line-derived neurotrophic factor, basic fibroblast growt h factor, brain-derived neurotrophic factor, and neurotrophin-3 direct ly induced Fos expression in differently sized, yet overlapping, popul ations of tyrosine hydroxylase-immunoreactive dopaminergic neurons. In an additional subpopulation of dopaminergic neurons, neurotrophin-3 i nduced fos-lacZ expression indirectly through a glutamate-mediated act ivation of N-methyl-D-aspartate receptors. Consistent with their propo sed glial-mediated mode of action, transforming growth factor cc and p latelet-derived growth factor induced Fos expression predominantly in glia but only in a very small number of dopaminergic neurons. These fi ndings demonstrate that individual dopaminergic neurons represent the direct targets of different sets of extracellular growth factors. Our findings further establish that growth factors affect dopaminergic neu rons by indirect mechanisms which require specific cell-cell communica tion. These data also suggest a potential role for growth factors in t he establishment of the morphological and functional diversity of midb rain dopaminergic neurons. Copyright (C) 1996 IBRO. Published by Elsev ier Science Ltd.