TGF-β promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8

Impaired neuronal survival is a key event in the development of degenerative diseases, such as Parkinson's disease (PD). Here we show that transforming growth factor beta (TGF-β) acts directly on rat E14 midbrain dopaminergic neurons in vitro, its survival-promoting effect being not mediated by BDNF, NT-3, or GDNF. Treatment with TGF-β, sonic hedgehog (Shh), or fibroblast growth factor-8 (FGF8) significantly increased number of tyrosine hydroxylase (TH)-immunoreactive neurons after 7 days, whereas application of these factors added together further increased number of TH-positive neurons, compared to single-factor treatments. Neutralization of endogenous TGF-β, Shh, or FGF8 significantly reduced number of dopaminergic neurons. TGF-β treatment decreased number of apoptotic cells, having no effect on cell proliferation. Neutralization of TGF-β in vivo during chick E6-10 resulted in reduced number of midbrain dopaminergic neurons. The results suggest that TGF-β is required for survival of mesencephalic dopaminergic neurons acting in cooperation with Shh and FGF8.