Acquisition of the Midbrain Dopaminergic Neuronal Identity

Abstract

The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.

The Different Molecular Code in Generation of Dopaminergic Neurons from Astrocytes and Mesenchymal Stem Cells

“…In the last few decades, mechanisms involving the developmental process of DA neurons have been elaborately described. The establishment of DA neurons is orchestrated by intrinsic transcriptional factors and environmental cues with a number of stages: neuronal induction, regional patterning/specification, and DA induction [23,30,43,45,47,48]. Chemicals S/C/D [19], morphogens S/F8/F2 [24,25,49] and transcription-factor cocktail MLN [16,17,19,33], which have been reported in a series of studies, promoted the sequential developmental stages of DA generation (Figure 7).…”

“…Over the last few decades, a variety of in vitro induction paradigm was established for the induction into DA neurons, including multiple molecules affecting both the intrinsic transcriptional regulation and the extrinsic microenvironment state [21][22][23][24]. For example, the morphogens such as sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), and basic fibroblast growth factor (FGF2) represent the floor plate-based strategy for the induction into DA neurons [25,26] and are essential for the generation of stem cell-derived DA neurons [24,25,27]; meanwhile, these morphogens also were supplemented in induction paradigm of cell fate conversion of somatic cells to increase the efficiency of DA neurons [19].…”

Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

“…More recently, clinical and neurophysiological evidence revealed that dopaminergic dysfunction is also implicated in AD pathophysiology [21][22][23][24][25][26][27][28][29]. In a transgenic model of AD, Nobili et al [30] demonstrated a progressive degeneration of neurons from the ventral tegmental area (VTA) (i.e., a dopaminergic-rich structure located in the midbrain) [31], which correlated behaviourally with reward and memory functions [30,32]. Notably, the mesocortico-limbic system, which is strictly involved in reward [33,35], as well as in executive and memory functions [30,36,37] stems from dopamine neurons located in the VTA midbrain region.…”

Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

“…Of these subsets, the neuroanatomically distinct substantia nigra (SNc) and ventral tegmental area (VTA) are best known, mainly due to the selective degeneration of the SNc during Parkinson’s disease (PD) [ 9 ]. The specification of the different subsets in the mdDA system is dependent on a unique set of transcription factors and signaling cascades during development [ 4 , 5 , 6 , 7 , 8 , 10 ], although knowledge of the factors that are important during subset specification is currently insufficient.…”