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.
Highlights
The mesodiencephalic dopaminergic group of neurons is involved in motor control, motivation, reward, and addiction
MdDA neurons are defined by the expression of general markers, like tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine (DA) production, vesicular monoamine transporter 2 (VMAT2), and paired-like homeodomain 3 (PITX3), and subset-specific markers, like dopamine transporter (DAT), aldehyde dehydrogenase 2 (AHD2), and pre-B-cell leukemia homeobox 3 (PBX3) for neurons of the substantia nigra (SN), and cholecystokinin (CCK) and WW domain-containing oxidoreductase (WWOX) as markers for neurons of the ventral tegmental area (VTA) [3,4,7,8]
We aim to describe the life of an mesodiencephalic dopaminergic (mdDA) neuron in the murine brain, from specification in the floor plate (FP) to differentiation into the various subsets in the mdDA group of neurons
Summary
The mesodiencephalic dopaminergic (mdDA) group of neurons is involved in motor control, motivation, reward, and addiction. MdDA neurons are defined by the expression of general markers, like tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine (DA) production, vesicular monoamine transporter 2 (VMAT2), and paired-like homeodomain 3 (PITX3), and subset-specific markers, like dopamine transporter (DAT), aldehyde dehydrogenase 2 (AHD2), and pre-B-cell leukemia homeobox 3 (PBX3) for neurons of the SN, and cholecystokinin (CCK) and WW domain-containing oxidoreductase (WWOX) as markers for neurons of the VTA [3,4,7,8]. We will try to link the development of the mdDA neuronal population to immune system development, as both systems comprise different subsets of cells, which are derived from floor plate (FP)-derived progenitors
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