Figure 1.

Spatial and temporal developmental stages leading to mesodiencephalic dopaminergic neurogenesis. (A) Sagittal and coronal schematic sections showing the region in the developing central nervous system where mesodiencephalic dopaminergic (mdDA) neurons are born. Anterior-posterior patterning leads to the genesis of morphogenetic domains: telencephalon (Tel), rostral diencephalon (RD), midbrain (M) and hindbrain (H), whereas dorsal-ventral patterning results in crosswise subdivisions in the brain: floor plate (FP), basal plate (BP), alar plate (AP) and roof plate. The mdDA area encompasses the midbrain and prosomeres (P) 1 to 3. The floor plate is divided in three main areas: the ventricular zone (VZ), the intermediate zone (IZ) and the marginal zone (MZ). (B) Molecular cascades leading to mdDA neurogenesis, illustrated by three different stages from top to bottom. The key genes driving mdDA development are represented. En1 and Wnt signaling are required already in early development, being essential throughout mdDA development, from early patterning up to the induction of mdDA neurons. Although we placed En1 in all these developmental stages, a molecular characterization of how En1 contributes to each of these has not yet been performed. It remains to be seen as well whether Wnt signaling is active in a settled mdDA neuron (after embryonic day (E)14). The progenitor pool is located in the VZ and its progeny migrates to the IZ, where it differentiates into post-mitotic mdDA precursors, expressing Nurr1 and L-aromatic amino acid decarboxylase (Aadc). Later on, after E12, mdDA neurons start to differentiate, expressing mdDA key identity genes like Pitx3, Th and Vmat2. The differentiated settled mdDA neurons localize in the MZ.