Location and size of dopaminergic and serotonergic cell populations are controlled by the position of the midbrain-hindbrain organizer
Open accessAbstract
Midbrain dopaminergic and hindbrain serotonergic neurons play an important role in the modulation of behavior and are involved in a series of neuropsychiatric disorders. Despite the importance of these cells, little is known about the molecular mechanisms governing their development. During embryogenesis, midbrain dopaminergic neurons are specified rostral to the midbrain-hindbrain organizer (MHO), and hindbrain serotonergic neurons are specified caudal to it. We report that in transgenic mice in which Otx2 and accordingly the MHO are shifted caudally, the midbrain dopaminergic neuronal population expands to the ectopically positioned MHO and is enlarged. Complementary, the extension of the hindbrain serotonergic cell group is decreased. These changes are preserved in adulthood, and the additional, ectopic dopaminergic neurons project to the striatum, which is a proper dopaminergic target area. In addition, in mutants in which Otx2 and the MHO are shifted rostrally, dopaminergic and serotonergic neurons are relocated at the newly positioned MHO. However, in these mice, the size ratio between these two cell populations is changed in favor of the serotonergic cell population. To investigate whether the position of the MHO during embryogenesis is also of functional relevance for adult behavior, we tested mice with a caudally shifted MHO and report that these mutants show a higher locomotor activity. Together, we provide evidence that the position of the MHO determines the location and size of midbrain dopaminergic and hindbrain serotonergic cell populations in vivo. In addition, our data suggest that the position of the MHO during embryogenesis can modulate adult locomotor activity.
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The boundaries of the dopamine primordium are defined by transcription factor expression: the caudal extent by the Otx2/Gbx2 boundary, the rostral extent by the En1/Dbx1 boundary, and the dorsal extent by the Lmx1a/Nkx6.1 boundary.
“The caudal extent is defined by the Otx2/Gbx2 boundary coincident with the morphological mid-hindbrain boundary [74]. The rostral extent is defined by the En1/Dbx1 gene expression boundary which is located in the diencephalic region [75–78]. The dorsal extent is defined by the Lmx1a/Nkx6.1 gene expression boundary [71,79–81].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [74]
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- Authors
- Brodski, C., Weisenhorn, D. M. V., Signore, M., Sillaber, I., Oesterheld, M., Broccoli, V., Acampora, D., Simeone, A., & Wurst, W.
- Affiliations
- Helmholtz Munich (DE)
- King's College London (GB)
- Max Planck Society (DE)
- IRCCS Ospedale San Raffaele (IT)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-05-15
- Volume
- 23
- Issue
- 10
- Pages
- 4199-4207
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6741088
- OpenAlex
- W1650647918
- Cited by
- 131
- References
- 45
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 9 · 2014: 8 · 2013: 5 · 2012: 8
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Wellcome Trust (062642)
- Deutsche Forschungsgemeinschaft
- Consiglio Nazionale delle Ricerche
- Fondation Bettencourt Schueller
- Medical Research Council
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- dopaminergic neurons, serotonergic neurons, Otx2, neuronal specification, neuronal migration, striatal projections, locomotor activity, embryonic development, transgenic mice
- MeSH terms
- Animals, Behavior, Animal, Brain Mapping, Dopamine, Female, Male, Mesencephalon, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Rhombencephalon, Serotonin, Trans-Activators, Homeodomain Proteins, Gene Expression Regulation, Developmental, Mice, Congenic, Organizers, Embryonic, Mice, Otx Transcription Factors
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