Epigenetic cues in midbrain dopaminergic neuron development.

Midbrain dopaminergic (DA) neurons subserve complex and varied neural functions in vertebrate CNS. Their progenitors give rise to DA neurons by the action of two extracellular inducers, Sonic Hedgehog and FGF8. After this first commitment, the function of selectively activated transcription factors, like the orphan steroid nuclear receptor Nurr1, is required for DA final determination. Subsequently, DA function is selectively modulated by specific interaction with the developing striatal target tissue. Committed and determined DA neurons express the key genes involved in DA neurotransmission at different times in development. Synthesis and intracellular accumulation of DA is achieved shortly after expression of Nurr1, while high affinity uptake, responsible for ending the neurotransmission, takes place after a few days. Cell contacts between the presynaptic DA neurons and target striatal neurons are apparently necessary for the fine modulation of DA function, in vivo and in vitro.