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Development of Dopaminergic Neurons

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 26529

Special Issue Editor

Special Issue Information

Dear Colleagues,

Dopaminergic neurons located in the mammalian ventral midbrain have attracted the attention of many biomedical researchers due to their effect in severe human neuropsychiatric and neurodegenerative disorders. There are four major signalling pathways which play critical roles during the development of the midbrain dopaminergic (mDA) neurons. In spite of the intense research conducted in recent years, we have achieved little understanding related to the crosstalk and the interaction between those four major signalling pathways and how they promote the development of mDA neurons in the mammalian embryo. This has been a very exciting research field and a number of questions remain answering:

(1) Which cellular and molecular mechanisms constitute the basis for the programming of the development of VTA DA neurons versus SNc DA neurons in vivo?

2) What could be the explanation for the vulnerability of some types of mDA neurons in some neurodegenerative disorders?

(3) What will be the efficacy and safety outcomes of the clinical trials using human stem cell-derived mDA neurons?

Contributions to this Special Issue will provide new insights into the mechanisms of action of the development of DA neurons and for the modelling and drug screening of the disorders mentioned above in the basic and clinical research.

Dr. Yasemin M. Akay
Guest Editor

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Keywords

  • neuron
  • dopamine
  • mDA
  • signalling pathways
  • human stem cell

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Published Papers (9 papers)

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Research

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16 pages, 1559 KiB  
Article
LPS-Induced Coagulation and Neuronal Damage in a Mice Model Is Attenuated by Enoxaparin
by Shani Berkowitz, Shany Guly Gofrit, Shay Anat Aharoni, Valery Golderman, Lamis Qassim, Zehavit Goldberg, Amir Dori, Nicola Maggio, Joab Chapman and Efrat Shavit-Stein
Int. J. Mol. Sci. 2022, 23(18), 10472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810472 - 09 Sep 2022
Cited by 2 | Viewed by 1509
Abstract
Background. Due to the interactions between neuroinflammation and coagulation, the neural effects of lipopolysaccharide (LPS)-induced inflammation (1 mg/kg, intraperitoneal (IP), n = 20) and treatment with the anti-thrombotic enoxaparin (1 mg/kg, IP, 15 min, and 12 h following LPS, n = 20) were studied [...] Read more.
Background. Due to the interactions between neuroinflammation and coagulation, the neural effects of lipopolysaccharide (LPS)-induced inflammation (1 mg/kg, intraperitoneal (IP), n = 20) and treatment with the anti-thrombotic enoxaparin (1 mg/kg, IP, 15 min, and 12 h following LPS, n = 20) were studied in C57BL/6J mice. Methods. One week after LPS injection, sensory, motor, and cognitive functions were assessed by a hot plate, rotarod, open field test (OFT), and Y-maze. Thrombin activity was measured with a fluorometric assay; hippocampal mRNA expression of coagulation and inflammation factors were measured by real-time-PCR; and serum neurofilament-light-chain (NfL), and tumor necrosis factor-α (TNF-α) were measured by a single-molecule array (Simoa) assay. Results. Reduced crossing center frequency was observed in both LPS groups in the OFT (p = 0.02), along with a minor motor deficit between controls and LPS indicated by the rotarod (p = 0.057). Increased hippocampal thrombin activity (p = 0.038) and protease-activated receptor 1 (PAR1) mRNA (p = 0.01) were measured in LPS compared to controls, but not in enoxaparin LPS-treated mice (p = 0.4, p = 0.9, respectively). Serum NfL and TNF-α levels were elevated in LPS mice (p < 0.05) and normalized by enoxaparin treatment. Conclusions. These results indicate that inflammation, coagulation, neuronal damage, and behavior are linked and may regulate each other, suggesting another pharmacological mechanism for intervention in neuroinflammation. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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27 pages, 3732 KiB  
Article
CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival
by Ave Eesmaa, Li-Ying Yu, Helka Göös, Tatiana Danilova, Kristofer Nõges, Emmi Pakarinen, Markku Varjosalo, Maria Lindahl, Päivi Lindholm and Mart Saarma
Int. J. Mol. Sci. 2022, 23(16), 9489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169489 - 22 Aug 2022
Cited by 11 | Viewed by 2654
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson’s disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but [...] Read more.
Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson’s disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function. We used tunicamycin to induce ER stress in mice in vivo and used cultured primary neurons and found that CDNF expression is regulated by ER stress in vivo and that the involvement of UPR pathways is important for the neuroprotective function of CDNF. Moreover, we used AP-MS and BiFC to perform the first interactome screening for CDNF and report novel binding partners of CDNF. These findings allowed us to hypothesize that CDNF protects neurons from ER-stress-inducing agents by modulating UPR signaling towards cell survival outcomes. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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15 pages, 4584 KiB  
Article
Toxic and Phenotypic Effects of AAV_Cre Used to Transduce Mesencephalic Dopaminergic Neurons
by Larissa Erben, Jacqueline P. Welday, Ricardo Murphy and Andres Buonanno
Int. J. Mol. Sci. 2022, 23(16), 9462; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169462 - 21 Aug 2022
Cited by 6 | Viewed by 1956
Abstract
A popular approach to spatiotemporally target genes using the loxP/Cre recombination system is stereotaxic microinjection of adeno-associated virus (AAV) expressing Cre recombinase (AAV_Cre) in specific neuronal structures. Here, we report that AAV_Cre microinjection in the ventral tegmental area (VTA) of ErbB4 Cyt-1-floxed [...] Read more.
A popular approach to spatiotemporally target genes using the loxP/Cre recombination system is stereotaxic microinjection of adeno-associated virus (AAV) expressing Cre recombinase (AAV_Cre) in specific neuronal structures. Here, we report that AAV_Cre microinjection in the ventral tegmental area (VTA) of ErbB4 Cyt-1-floxed (ErbB4 Cyt-1fl/fl) mice at titers commonly used in the literature (~1012–1013 GC/mL) can have neurotoxic effects on dopaminergic neurons and elicit behavioral abnormalities. However, these effects of AAV_Cre microinjection are independent of ErbB4 Cyt-1 recombination because they are also observed in microinjected wild-type (WT) controls. Mice microinjected with AAV_Cre (1012–1013 GC/mL) exhibit reductions of tyrosine hydroxylase (TH) and dopamine transporter (DAT) expression, loss of dopaminergic neurons, and they behaviorally become hyperactive, fail to habituate in the open field and exhibit sensorimotor gating deficits compared to controls microinjected with AAV_GFP. Importantly, these AAV_Cre non-specific effects are: (1) independent of serotype, (2) occur with vectors expressing either Cre or Cre-GFP fusion protein and (3) preventable by reducing viral titers by 1000-fold (1010 GC/mL), which retains sufficient recombination activity to target floxed genes. Our studies emphasize the importance of including AAV_Cre-injected WT controls in experiments because recombination-independent effects on gene expression, neurotoxicity and behaviors could be erroneously attributed to consequences of gene ablation. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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16 pages, 5682 KiB  
Article
Investigating the Influence of GABA Neurons on Dopamine Neurons in the Ventral Tegmental Area Using Optogenetic Techniques
by Yasumi Ohta, Takaaki E. Murakami, Mamiko Kawahara, Makito Haruta, Hironari Takehara, Hiroyuki Tashiro, Kiyotaka Sasagawa, Jun Ohta, Metin Akay and Yasemin M. Akay
Int. J. Mol. Sci. 2022, 23(3), 1114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031114 - 20 Jan 2022
Cited by 5 | Viewed by 4285
Abstract
Dopamine (DA) is the key regulator of reward behavior. The DA neurons in the ventral tegmental area (VTA) and their projection areas, which include the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala, play a primary role in the process of reward-driven behavior [...] Read more.
Dopamine (DA) is the key regulator of reward behavior. The DA neurons in the ventral tegmental area (VTA) and their projection areas, which include the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala, play a primary role in the process of reward-driven behavior induced by the drugs of addiction, including nicotine and alcohol. In our previous study, we developed a novel platform consisting of micro-LED array devices to stimulate a large area of the brain of rats and monkeys with photo-stimulation and a microdialysis probe to estimate the DA release in the PFC. Our results suggested that the platform was able to detect the increased level of dopamine in the PFC in response to the photo-stimulation of both the PFC and VTA. In this study, we used this platform to photo-stimulate the VTA neurons in both ChrimsonR-expressing (non-specific) wild and dopamine transporter (DAT)-Cre (dopamine specific) mice, and measured the dopamine release in the nucleus accumbens shell (NAcShell). We measured the DA release in the NAcShell in response to optogenetic stimulation of the VTA neurons and investigated the effect of GABAergic neurons on dopaminergic neurons by histochemical studies. Comparing the photo-stimulation frequency of 2 Hz with that of 20 Hz, the change in DA concentration at the NAcShell was greater at 20 Hz in both cases. When ChrimsonR was expressed specifically for DA, the release of DA at the NAcShell increased in response to photo-stimulation of the VTA. In contrast, when ChrimsonR was expressed non-specifically, the amount of DA released was almost unchanged upon photo-stimulation. However, for nonspecifically expressed ChrimsonR, intraperitoneal injection of bicuculline, a competitive antagonist at the GABA-binding site of the GABAA receptor, also significantly increased the release of DA at the NAcShell in response to photo-stimulation of the VTA. The results of immunochemical staining confirm that GABAergic neurons in the VTA suppress DA activation, and also indicate that alterations in GABAergic neurons may have serious downstream effects on DA activity, NAcShell release, and neural adaptation of the VTA. This study also confirms that optogenetics technology is crucial to study the relationship between the mesolimbic dopaminergic and GABAergic neurons in a neural-specific manner. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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17 pages, 7468 KiB  
Article
Nkx2.9 Contributes to Mid-Hindbrain Patterning by Regulation of mdDA Neuronal Cell-Fate and Repression of a Hindbrain-Specific Cell-Fate
by Willemieke M. Kouwenhoven, Lars von Oerthel, Maria Gruppilo, Jianmin Tian, Cindy M. R. J. Wagemans, Imke G. J. Houwers, Joseph Locker, Simone Mesman and Marten P. Smidt
Int. J. Mol. Sci. 2021, 22(23), 12663; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312663 - 23 Nov 2021
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Abstract
Nkx2.9 is a member of the NK homeobox family and resembles Nkx2.2 both in homology and expression pattern. However, while Nkx2.2 is required for development of serotonergic neurons, the role of Nkx2.9 in the mid-hindbrain region is still ill-defined. We have previously shown [...] Read more.
Nkx2.9 is a member of the NK homeobox family and resembles Nkx2.2 both in homology and expression pattern. However, while Nkx2.2 is required for development of serotonergic neurons, the role of Nkx2.9 in the mid-hindbrain region is still ill-defined. We have previously shown that Nkx2.9 expression is downregulated upon loss of En1 during development. Here, we determined whether mdDA neurons require Nkx2.9 during their development. We show that Nkx2.9 is strongly expressed in the IsO and in the VZ and SVZ of the embryonic midbrain, and the majority of mdDA neurons expressed Nkx2.9 during their development. Although the expression of Dat and Cck are slightly affected during development, the overall development and cytoarchitecture of TH-expressing neurons is not affected in the adult Nkx2.9-depleted midbrain. Transcriptome analysis at E14.5 indicated that genes involved in mid- and hindbrain development are affected by Nkx2.9-ablation, such as Wnt8b and Tph2. Although the expression of Tph2 extends more rostral into the isthmic area in the Nkx2.9 mutants, the establishment of the IsO is not affected. Taken together, these data point to a minor role for Nkx2.9 in mid-hindbrain patterning by repressing a hindbrain-specific cell-fate in the IsO and by subtle regulation of mdDA neuronal subset specification. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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20 pages, 5430 KiB  
Article
The Different Molecular Code in Generation of Dopaminergic Neurons from Astrocytes and Mesenchymal Stem Cells
by Nana Wang, Xingrui Ji, Yue Wu, Shaocong Zhou, Huiyu Peng, Jingwen Wang, Shuang Yu and Jingzhong Zhang
Int. J. Mol. Sci. 2021, 22(22), 12141; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212141 - 09 Nov 2021
Cited by 2 | Viewed by 1967
Abstract
Transplantation of exogenous dopaminergic (DA) neurons is an alternative strategy to replenish DA neurons that have lost along the course of Parkinson’s disease (PD). From the perspective of ethical acceptation, the source limitations, and the intrinsic features of PD pathology, astrocytes (AS) and [...] Read more.
Transplantation of exogenous dopaminergic (DA) neurons is an alternative strategy to replenish DA neurons that have lost along the course of Parkinson’s disease (PD). From the perspective of ethical acceptation, the source limitations, and the intrinsic features of PD pathology, astrocytes (AS) and mesenchymal stem cells (MSCs) are the two promising candidates of DA induction. In the present study, we induced AS or MSCs primary culture by the combination of the classical transcription-factor cocktails Mash1, Lmx1a, and Nurr1 (MLN), the chemical cocktails (S/C/D), and the morphogens SHH, FGF8, and FGF2 (S/F8/F2); the efficiency of induction into DA neurons was further analyzed by using immunostaining against the DA neuronal markers. AS could be efficiently converted into the DA neurons in vitro by the transcriptional regulation of MLN, and the combination with S/C/D or S/F8/F2 further increased the conversion efficiency. In contrast, MSCs from umbilical cord (UC-MSCs) or adipose tissue (AD-MSCs) showed moderate TH immunoreactivity after the induction with S/F8/F2 instead of with MLN or S/C/D. Our data demonstrated that AS and MSCs held lineage-specific molecular codes on the induction into DA neurons and highlighted the unique superiority of AS in the potential of cell replacement therapy for PD. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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14 pages, 1481 KiB  
Article
Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation
by Xiaoying Cui, Renata Ap. Nedel Pertile, Zilong Du, Wei Wei, Zichun Sun, Darryl W. Eyles and James P. Kesby
Int. J. Mol. Sci. 2021, 22(14), 7268; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147268 - 06 Jul 2021
Cited by 3 | Viewed by 2729
Abstract
The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is [...] Read more.
The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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Review

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23 pages, 1035 KiB  
Review
Roles of Transcription Factors in the Development and Reprogramming of the Dopaminergic Neurons
by Lulu Tian, Murad Al-Nusaif, Xi Chen, Song Li and Weidong Le
Int. J. Mol. Sci. 2022, 23(2), 845; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020845 - 13 Jan 2022
Cited by 17 | Viewed by 4450
Abstract
The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement [...] Read more.
The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement neurological disorders, Parkinson’s disease (PD). How these cells die and regenerate are two of the most hotly debated PD research topics. As for the latter, it has been long known that a series of transcription factors (TFs) involves the development of mdDA neurons, specifying cell types and controlling developmental patterns. In vitro and in vivo, TFs regulate the expression of tyrosine hydroxylase, a dopamine transporter, vesicular monoamine transporter 2, and L-aromatic amino acid decarboxylase, all of which are critical for dopamine synthesis and transport in dopaminergic neurons (DA neurons). In this review, we encapsulate the molecular mechanism of TFs underlying embryonic growth and maturation of mdDA neurons and update achievements on dopaminergic cell therapy dependent on knowledge of TFs in mdDA neuronal development. We believe that a deeper understanding of the extrinsic and intrinsic factors that influence DA neurons’ fate and development in the midbrain could lead to a better strategy for PD cell therapy. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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19 pages, 3536 KiB  
Review
The Dopaminergic Control of Movement-Evolutionary Considerations
by Juan Pérez-Fernández, Marta Barandela and Cecilia Jiménez-López
Int. J. Mol. Sci. 2021, 22(20), 11284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011284 - 19 Oct 2021
Cited by 6 | Viewed by 3374
Abstract
Dopamine is likely the most studied modulatory neurotransmitter, in great part due to characteristic motor deficits in Parkinson’s disease that arise after the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). The SNc, together with the ventral tegmental area [...] Read more.
Dopamine is likely the most studied modulatory neurotransmitter, in great part due to characteristic motor deficits in Parkinson’s disease that arise after the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). The SNc, together with the ventral tegmental area (VTA), play a key role modulating motor responses through the basal ganglia. In contrast to the large amount of existing literature addressing the mammalian dopaminergic system, comparatively little is known in other vertebrate groups. However, in the last several years, numerous studies have been carried out in basal vertebrates, allowing a better understanding of the evolution of the dopaminergic system, especially the SNc/VTA. We provide an overview of existing research in basal vertebrates, mainly focusing on lampreys, belonging to the oldest group of extant vertebrates. The lamprey dopaminergic system and its role in modulating motor responses have been characterized in significant detail, both anatomically and functionally, providing the basis for understanding the evolution of the SNc/VTA in vertebrates. When considered alongside results from other early vertebrates, data in lampreys show that the key role of the SNc/VTA dopaminergic neurons modulating motor responses through the basal ganglia was already well developed early in vertebrate evolution. Full article
(This article belongs to the Special Issue Development of Dopaminergic Neurons)
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