Origin and specification of mDA neurons

Specification of neuronal fates begins with the acquisition of anterior-posterior (A/P)

Fig. 1. Schematic representation of the anterior/posterior (A) and dorsal/ventral (B) patterning of the brain and the emergence of mDA neurons (red) with specific identity to regional molecular coding. A Drawing of an E12.5 mouse brain in a sagittal plane showing the location of fully differentiated mDA neurons (red) in specific brain segments (M-P3). B Drawing of an E12.5 mouse midbrain in a coronal plane, showing the ventral localization of fully differentiated mDA neurons. Neurons are born in the ventricular zone across specific longitudinal domains (floor plate (FP, green), basal plate (BP, blue) or alar plate (AP, yellow)) and migrate ventrally (arrows) where they adopt the full dopaminergic phenotype and start to express Pitx3. Aq aqueduct; H hindbrain; M midbrain; MHB mid-hindbrain border (Isthmus); Pl-3 prosomere 1-3; RD rostral diencephalon; Tel telencepalon

Fig. 1. Schematic representation of the anterior/posterior (A) and dorsal/ventral (B) patterning of the brain and the emergence of mDA neurons (red) with specific identity to regional molecular coding. A Drawing of an E12.5 mouse brain in a sagittal plane showing the location of fully differentiated mDA neurons (red) in specific brain segments (M-P3). B Drawing of an E12.5 mouse midbrain in a coronal plane, showing the ventral localization of fully differentiated mDA neurons. Neurons are born in the ventricular zone across specific longitudinal domains (floor plate (FP, green), basal plate (BP, blue) or alar plate (AP, yellow)) and migrate ventrally (arrows) where they adopt the full dopaminergic phenotype and start to express Pitx3. Aq aqueduct; H hindbrain; M midbrain; MHB mid-hindbrain border (Isthmus); Pl-3 prosomere 1-3; RD rostral diencephalon; Tel telencepalon and dorsal-ventral (D/V) patterning in restricted domains of the neuronal plate (Fig. 1). D/V patterning causes longitudinal subdivisions in the brain (floor plate, basal plate and alar plate), whereas A/P patterning leads to neuromeric domains (forebrain, midbrain, isthmus and hindbrain; Puelles, 2001). The commitment of neuronal identity by a molecular code within progenitor cells in the ventricular zone and region-specific developmental cascades ultimately results in induction of distinct neuronal cell types, including mDA neurons (Fig. 1). In human embryos, mDA neurons in the SNc and VTA originate independently across several neuromeric domains and longitudinal subdivisions, and thus are not primarily unitary (Verney et al., 2001). Thus, the developmental origin of mDA neurons with respect to the longitudinal subdivisions and neuromeric domains in the brain, and the molecular codes within mDA subsets might determine the distinct features of these cells.

Concluding remarks

It becomes more and more clear that the mDA system harbors a multitude of specific functional neuronal units exemplified by region-specific molecular codes during development and in the adult. The role of Pitx3 in the development of SNc mDA neurons might link molecular codes to survival of mDA subsets, which can be exploited in the treatment of PD. Recently, it was shown that Pitx3 facilitates differentiation of mouse embryonic stem cells into the A9 cell group of mDA neurons, without affecting the total number of dopamine neurons (Chung et al., 2005), illustrating the importance of identifying the appropriate signals and factors that influence normal mDA development. Until now no molecular target genes of Pitx3 are identified and molecular processes initiated by Pitx3 remain unidentified. Therefore, further investigation is warranted to elucidate the role of Pitx3 in mDA neuronal development and maintenance.

S. M. Smits and M. P. Smidt: The role of Pitx3 in survival of midbrain dopaminergic neurons

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