Figure 1.

Schematics of the key players of mDA neuron development. Regionalisation of the neural tube (hindbrain (hb) brown, midbrain (mb) pink) establishes midbrain tissue identity via the inductive signals of Shh and Fgf8, which arise from the notochord (grey circle) and the midbrain-hindbrain border (blue) respectively, combined with Otx2 expression. This interaction enables midbrain ventral midline cells to respond to the later expression of the mDA neuron determination gene Lmx1a. Specification of the mDA neuronal identity occurs within the proliferative zone (grey) of the ventral midline. Here, Msx1 and Foxa2 promote generic neurogenesis via regulation of Ngn2 whilst Lmx1a, supported by Msx1, specifies mDA neuron cell fate. As these mDA neuron progenitors become postmitotic and enter the intermediate zone (yellow), they begin to express the pan neuronal marker Tuj1 and, subsequently, the DA neuron transmitter regulator, Nurr1. Lmx1b and Wnt1 positively control early Pitx3 expression in some Nurr1⁺ cells. The last stage in mDA neuronal differentiation proceeds as the Pitx3⁺ cells and the Th⁺ cells migrate ventrally into the peripheral zone (red). The ventrolaterally located Pitx3⁺Th^- cell subpopulations coalesce leaving a Pitx3^- Th⁺ cell group in a medial position. Eventually, the early Pitx3 expressing subpopulation migrates laterally to make up the neural population of the SNc and begin to express Th. The remaining medial, Th⁺, cells form the VTA. All Nurr1⁺ cells come to express Th and Pitx3. En1 and En2 maintain survival of the mature mDA neurons in the ventral midbrain. [Colours highlight the postulated region of activity of the genes in the corresponding colour.]