Transcription factors in the development of midbrain dopamine neurons.

The development of midbrain dopamine (DA) neurons follows a number of stages marked by distinct events. After preparation of the region by signals that provide induction and patterning, at least two cascades of transcription factors contribute to the fully matured midbrain DA systems. One cascade involving the nuclear receptor Nurr1 is required to synthesize the neurotransmitter DA; the enzyme tyrosine hydroxylase (TH) depends on it. The other cascade involves homeobox genes. Lmx1b and engrailed genes are expressed before the genesis of DA neurons and maintain their expression in these neurons. Lmx1b drives Ptx3, which is the latest transcription factor known to be induced. Its induction coincides with that of TH. Disruption of the function of Ptx3 affects the formation of the substantia nigra (SN) and alters the anatomical organization of the midbrain DA systems. While each cascade contributes to a specific aspect of DA neurons, both cascades are required for survival during development, indicating that the maintenance of DA neurons is delicately dependent on the appropriate activity of multiple transcriptional cascades.