TRANSFORMING GROWTH-FACTOR-BETA PROMOTES SURVIVAL OF MIDBRAIN DOPAMINERGIC-NEURONS AND PROTECTS THEM AGAINST N-METHYL-4-PHENYLPYRIDINIUM ION TOXICITY

Transforming growth factors beta are multifunctional proteins and regu lators of cell proliferation and differentiation. Transforming growth factor-beta s have the capacity to rescue adult neurons from ischemia- and glutamate-induced cell death and are prominent in the embryonic a nd adult brain including striatum and substantia nigra. In the present study we show that transforming growth factors-beta 1, -2, and -3 pro mote, in a dose-dependent fashion, in vitro survival of tyrosine hydro xylase-immunoreactive dopaminergic neurons isolated from the embryonic rat mesencephalon floor. The magnitude of the effect, which was half- maximal at a concentration of 20 pM, was identical for all three trans forming growth factor-isoforms and matched that of fibroblast growth f actor-2. Unlike fibroblast growth factor-2, however, transforming grow th factor-beta s did not increase numbers of astroglial cells visualiz ed by using antibodies to glial fibrillary acidic protein, and bad no effect on cell proliferation monitored by incorporation of BrdUrd. Tra nsforming growth factor-beta s were significantly more potent than fib roblast growth factor-2 in protecting dopaminergic neurons against N-m ethyl-4-phenylpyridinium ion toxicity. RT-PCR analysis indicated that the effect of transforming growth factor-beta s is not mediated by gli al cell-derived neurotrophic factor, which was not detectable in cultu res at various time points. On the other hand transforming growth fact or-beta 2 mRNA could be detected in freshly isolated and cultured mese ncephalic cells, and its immunoreactivity has also been demonstrated i n the embryonic day 14 mesencephalon floor. We conclude that transform ing growth factor-beta has trophic and protective effects on developin g dopaminergic neurons. The effects, unlike those of fibroblast growth factor-2 and many other mitogens supporting dopaminergic neurons, are not mediated by astroglial cells and not accompanied by an increase i n cell proliferation.