Sox6 and Otx2 control the specification of substantia nigra and ventral tegmental area dopamine neurons
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Distinct midbrain dopamine (mDA) neuron subtypes are found in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA), but it is mainly SNc neurons that degenerate in Parkinson's disease. Interest in how mDA neurons develop has been stimulated by the potential use of stem cells in therapy or disease modeling. However, very little is known about how specific dopaminergic subtypes are generated. Here, we show that the expression profiles of the transcription factors Sox6, Otx2, and Nolz1 define subpopulations of mDA neurons already at the neural progenitor cell stage. After cell-cycle exit, Sox6 selectively localizes to SNc neurons, while Otx2 and Nolz1 are expressed in a subset of VTA neurons. Importantly, Sox6 ablation leads to decreased expression of SNc markers and a corresponding increase in VTA markers, while Otx2 ablation has the opposite effect. Moreover, deletion of Sox6 affects striatal innervation and dopamine levels. We also find reduced Sox6 levels in Parkinson's disease patients. These findings identify Sox6 as a determinant of SNc neuron development and should facilitate the engineering of relevant mDA neurons for cell therapy and disease modeling.
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A substantial SOX6+ ALDH1A1- population is located more dorsal to ALDH1A1+ neurons in the substantia nigra pars compacta, the parabrachial pigmented region of the ventral tegmental area, and the retrorubral area.
“In immunolabeling studies, there is a substantial SOX6+ population that is ALDH1A1- [13,14,26]; these cells are located more dorsal to the ALDH1A1+ neurons in the SNc, the parabrachial pigmented (PBP) region of the VTA and the RR.”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [26]
Sox6 is expressed in the medial aspect of the dopamine progenitor pool, and this progenitor pool has been proposed to be the source of the majority of the substantia nigra pars compacta but not the ventral tegmental area.
“More recently, Sox6 has been shown to be expressed in the medial aspect of the progenitor pool, and based on immunolabeling experiments, this progenitor pool has been proposed to be the source of the majority of the SNc but not the VTA [26].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [26]
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Self-citationClassification of midbrain dopamine neurons using single-cell gene expression profiling approaches
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- Authors
- Panman, L., Papathanou, M., Laguna, A., Oosterveen, T., Volakakis, N., Acampora, D., Kurtsdotter, I., Yoshitake, T., Kehr, J., Joodmardi, E., Muhr, J., Simeone, A., Ericson, J., & Perlmann, T.
- Affiliations
- Ludwig Cancer Research (SE)
- Ludwig Cancer Research (BE)
- Istituto Neurologico Mediterraneo (IT)
- Karolinska Institutet (SE)
- Corresponding author
- Panman, Lia
- Perlmann, Thomas
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 8
- Issue
- 4
- Pages
- 1018-1025
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W1969276438
- Cited by
- 143
- References
- 44
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 13 · 2023: 12 · 2022: 15 · 2021: 15 · 2020: 19 · 2019: 16 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 1
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Commission
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- SOX6, Otx2, midbrain dopaminergic neurons, substantia nigra pars compacta, ventral tegmental area, transcription factors, neural progenitor cells, Parkinson's disease, cell therapy, disease modeling
- MeSH terms
- Animals, Humans, Mice, Transgenic, Organ Specificity, Substantia Nigra, Ventral Tegmental Area, Body Patterning, Otx Transcription Factors, SOXD Transcription Factors, Dopaminergic Neurons
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