Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain
Abstract
Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinsons disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the transcription factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors. By using mouse models and immunohistochemistry, we have investigated whether Otx2 is expressed also in post-mitotic mdDA neurons. Our data reveal that Otx2 is expressed in post-mitotic mesDA neurons during mid-late gestation and in the adult brain. Remarkably, Otx2 expression is sharply excluded from mdDA neurons of the SN and is restricted to a relevant fraction of VTA neurons. Otx2+-TH+ neurons are concentrated to the ventral part of the VTA. Combined expression with other regionalized VTA markers shows that Otx2+-TH+ neurons are prevalently Girk2- and Calb+ and among these, those located in the medial and ventralmost portion of the VTA are also Ahd2+. These findings indicate that Otx2 represents the first transcription factor with a proven role in mdDA neurogenesis whose expression discriminates between SN and a relevant proportion of VTA neurons. This supports the possibility that Otx2 may act as a post-mitotic selector controlling functional features (e.g. identity and/or survival) of a relevant fraction of VTA neurons in the adult.
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Otx2+, Aldh1a1+ dopamine neurons are located in the ventromedial ventral tegmental area.
“Otx2+, Aldh1a1+ DA neurons in the ventromedial VTA”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [31]
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InfluentialState of the Art in Sub-Phenotyping Midbrain Dopamine Neurons
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BackgroundSpecific expression pattern of a novel Otx2 splicing variant during neural differentiation
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OTX2 impedes self–renewal of porcine iPS cells through downregulation of NANOG expression
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“…Girk2 and DAT are the downstream targets of OTX2, and these two proteins are also involved in the maintenance of function and survival of mDANs (Di Salvio et al., 2010a, 2010b), we further examined DAT expression in the midbrain and striatum, and Girk2 expression in the midbrain by Western blot…”
BackgroundInfluentialMolecular Determinants of A9 Dopaminergic Neurons
Mishra, A. K., Dixit, S., Singh, A. L., Shukla, T., & Rizvi, S. I. (2025) · NeuroMolecular Medicine · doi:10.1007/s12017-025-08861-1 · Cited by 6 · see citing works
“This differential regulation is essential for defining the molecular identity of DA subgroups, as Otx2-expressing neurons in the VTA display enhanced survival properties compared to Otx2-negative A9 neurons (Di Salvio et al., 2010).”
Benitez, J. A., Cheng, S., Kee, N., Cao, M., Wang, M., Deng, Q., & Hedlund, E. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/334417 · Cited by 6 · see citing works
“…label SNc e.g. Aldh1a7, Sox6, Cbln1, Vav3, Atp2a3 and VTA e.g. Calb1, Otx2, Crym, Cadm1, Marcks (Bifsha et al., 2014; Chung et al., 2005; Damier et al., 1999a; Di Salvio et al., 2010; Greene et al., 2005; Grimm et al., 2004; Nichterwitz et al., 2016; Panman et al., 2014) dopamine neurons.”
An in vivo and in vitro spatiotemporal profile of human midbrain development
Budinger, D., Puigdevall, P., Hall, G. T., Roth, C., Xenakis, T. A., Marrosu, E., Jerber, J., Domenico, A. D., Picco, F., Kilpinen, H., et al. (2026) · Nature Communications · doi:10.1038/s41467-025-67779-1 · Cited by 6 · see citing works
“At 16 PCW, we could identify the primordium of the SN and VTA within the mantel zone (MZ) of the basal plate, where TH+ mDA neurons occur for the fi rst time (Supp Fig.”
InfluentialXue, J., Li, Y., Qi, Y., Zhang, Z., & Tang, X. (2022) · NeuroToxicology · doi:10.1016/j.neuro.2022.05.013 · Cited by 5 · see citing works
Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegenerationPreprint
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“OTX2, the first transcription factor proven to have a role in mesencephalic-diencephalic dopaminergic (mdDA) neurogenesis [29], controls the development of several neuronal populations in themidbrain by regulating progenitor identity and neurogenesis [30].”
BackgroundOtx genes and seizure susceptibility
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“Otx2 expression is then maintained in postmitotic mesDA neurons during late embryogenesis and in the adult brain [25-27] .”
BackgroundDistinct roles of dopamine receptors in HIV latency reversal in a myeloid cell model
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“The DRD1 predicted top regulator OXT2 is a transcription factor that not only plays a role in the brain, in fl uencing the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis, but also plays a critical role in controlling chromatin structure (57 – 59).”
Big Regeneration Mechanisms via Systems Biology and Big Database Mining Methods
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LCM-seq identifies robust markers of vulnerable and resistant human midbrain dopamine neuronsPreprint
Benitez, J. A., Cheng, S., Kee, N., Cao, M., Deng, Q., & Hedlund, E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.03.023770 · Cited by 1 · see citing works
“…that appear to differentially label SNc e.g. Aldh1a7, Sox6, Cbln1, Vav3, Atp2a3 and VTA e.g. Calb1, Otx2, Crym, Cadm1 and Marcks (Damier et al. 1999a; Grimm et al. 2004; Chung et al. 2005; Greene et al. 2005; Di Salvio et al. 2010; Bifsha et al. 2014; Panman et al. 2014; Nichterwitz et al. 2016).”
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Determining the Role of Sonic Hedgehog in Establishing Midbrain Dopaminergic Neuron Subclasses
Kabanova, A. (2013) · bonndoc (University of Bonn)
Johansson, J. (2014) · Tampere University Institutional Repository (Tampere University)
Non-cell autonomous OTX2 transcription factor regulates anxiety-related behaviors in the mousePreprint
Vincent, C., Gilabert‐Juan, J., Alvarez‐Fischer, D., Nardo, A. A. D., Krebs, M., Pen, G. L., & Prochiantz, A. (2019) · HAL
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MicroRNA-148a regulates depressive-like behaviors in mice via the Otx2/Dopaminergic signaling axis
Tang, Y., Feng, H., Li, Y., Zhang, L., Qu, C., Zhu, T., Zhang, D., Wen, Y., Zeng, X., Zhang, Y., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03785-z
- Authors
- Di Salvio, M., Di Giovannantonio, L. G., Omodei, D., Acampora, D., & Simeone, A.
- Affiliations
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- Istituto Neurologico Mediterraneo (IT)
- Corresponding author
- Simeone, Antonio
- Venue
- The International Journal of Developmental Biology
- Publisher
- EHU Press
- Published
- 2010
- Volume
- 54
- Issue
- 5
- Pages
- 939-945
- ISSN
- 0214-6282 (ISSN-L)
- OpenAlex
- W2073751853
- Cited by
- 86
- References
- 19
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 5 · 2015: 10 · 2014: 9 · 2013: 8 · 2012: 8
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The International Journal of Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Roma
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Otx2, dopaminergic neurons, ventral tegmental area, substantia nigra, midbrain dopaminergic neurons, transcription factors, dopamine transporter, GIRK2, calbindin, neuronal identity, neurogenesis, Parkinson's disease
- MeSH terms
- Animals, Brain, Dopamine, Embryo, Mammalian, Immunohistochemistry, Mutation, Neurons, Time Factors, Ventral Tegmental Area, Gene Expression Regulation, Developmental, Gene Expression Profiling, Mice, Otx Transcription Factors
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