The role of Ret receptor tyrosine kinase in dopaminergic neuron development.

Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent trophic factors identified for promoting survival and function of dopaminergic (DA) neurons in the midbrain. Ret, a member of the receptor tyrosine kinase (RTK) superfamily transduces GDNF signaling. The role of Ret in the development of DA neurons is not clear however. Here we demonstrate the involvement of Ret in the DA neuron development both in vitro and in vivo. The dopamine transporter (DAT) gene was clearly induced in rat embryonic neural precursors that had been transfected with Ret. Temporary blockade of Ret expression in embryos using Ret antisense oligonucleotides (Ret-AS-ODN) in vivo led to reduced striatal DA content and a decrease of tyrosine hydroxylase (TH) positive fibers in the striatum. Additionally, some DA neurons in the substantia nigra (SN) underwent apoptotic cell death following the Ret-AS-ODN treatment. Taken together, the data suggest that normal function of Ret is required in vivo for the maturation of DA neurons, in particular for cell survival and fiber innervation. We further demonstrated Ret-induced expression of DAT in vitro.