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Review
. 2020 Jun 3;21(11):3995.
doi: 10.3390/ijms21113995.

Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration

Floriana Volpicelli  1 , Carla Perrone-Capano  1   2 , Gian Carlo Bellenchi  2   3 , Luca Colucci-D'Amato  4 , Umberto di Porzio  2
Affiliations
Review

Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration

Floriana Volpicelli et al. Int J Mol Sci. .

Abstract

The relatively few dopaminergic neurons in the mammalian brain are mostly located in the midbrain and regulate many important neural functions, including motor integration, cognition, emotive behaviors and reward. Therefore, alteration of their function or degeneration leads to severe neurological and neuropsychiatric diseases. Unraveling the mechanisms of midbrain dopaminergic (mDA) phenotype induction and maturation and elucidating the role of the gene network involved in the development and maintenance of these neurons is of pivotal importance to rescue or substitute these cells in order to restore dopaminergic functions. Recently, in addition to morphogens and transcription factors, microRNAs have been identified as critical players to confer mDA identity. The elucidation of the gene network involved in mDA neuron development and function will be crucial to identify early changes of mDA neurons that occur in pre-symptomatic pathological conditions, such as Parkinson's disease. In addition, it can help to identify targets for new therapies and for cell reprogramming into mDA neurons. In this essay, we review the cascade of transcriptional and posttranscriptional regulation that confers mDA identity and regulates their functions. Additionally, we highlight certain mechanisms that offer important clues to unveil molecular pathogenesis of mDA neuron dysfunction and potential pharmacological targets for the treatment of mDA neuron dysfunction.

Keywords: Parkinson’s disease; dopamine; microRNAs; midbrain; morphogens; transcription factors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the midbrain dopaminergic pathways. The figure illustrates in a schematic representation the two dopaminergic pathways originating from the midbrain (delimited by a red rectangle). The ventral tegmental area (VTA) and the substantia nigra (SN) in the adult ventral midbrain are visualized by anti-tyrosine hydroxylase antibodies. On the left: the nigrostriatal pathway connects the SN pars compacta in the midbrain with the dorsal striatum (i.e., caudate nucleus and putamen) in the forebrain. The main function of the nigrostriatal pathway is to control voluntary movement through basal ganglia motor loops. Degeneration of SN dopaminergic neurons leads to diminished concentrations of dopamine in the caudate-putamen. Degeneration of this pathway causes Parkinson’s disease (see text). On the right: the meso-cortico-limbic system pathway connects the VTA in the midbrain to the ventral striatum (i.e., nucleus accumbens) and to the prefrontal cortex. It regulates motivation, emotions, reward and cognitive functions. Dysfunction of this pathway is associated to schizophrenia, drug addiction, attention deficit hyperactive disorder (ADHD), depression and chronic pain (see text).
Figure 2
Figure 2
Genetic networks controlling midbrain dopaminergic neuron development in the mouse brain. The diagram summarizes the sequential stages and the molecules involved in mouse midbrain DA neuron embryonic development. The expression of transcription factors (TF) and secreted molecules involved in midbrain regional specification, induction, floor plate specification, differentiation and maturation of the mDA phenotype are indicated, at various embryonic (E) ages. Lines depict possible interactions among these molecules. Arrows indicate stimulatory effects, while perpendicular lines denote inhibitory effects. The orange area, delimited by a dotted line, clusters the TFs and molecules involved in anteroposterior patterning (see text). The light blue area, delimited by a dotted line, clusters the TFs involved in ventral patterning (see text). The green area, delimited by a dotted line, groups the TFs involved in midbrain floor plate specification (see text). The violet area, delimited by a dotted line, collects the TFs involved in mDA identity (see text).
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