Lmx1a and Lmx1b cooperate with Foxa2 to coordinate the specification of dopaminergic neurons and control of floor plate cell differentiation in the developing mesencephalon
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Mesencephalic dopaminergic (mesDA) neurons control movement and behavior, and their loss causes severe neurological disorders, such as Parkinson's disease. Recent studies have revealed that mesDA neurons originate from mesencephalic floor plate (FP) cells, which had been thought of as non-neurogenic organizer cells regulating regional patterning and axonal projections. Otx2 and its FP-specific downstream factor Lmx1a have been shown to be sufficient to confer neurogenic activity on FP cells and determine a mesDA fate. However, the mechanism underlying how these factors control mesDA development and how FP cells and mesDA neurons are coordinately specified are still largely unknown. In the present study, we obtained evidence that Lmx1a and Lmx1b cooperate with Foxa2 to specify mesDA neuron identity by gain-of-function approaches using transgenic mice. Lmx1a/b appeared to select a mesDA fate by suppressing red nucleus fate in the context of Foxa2-positive progenitors, at least in part, through repressing the Sim1-Lhx1 and Ngn1 pathways that inhibit proper mesDA differentiation. We also found that, in the mesencephalon, FP cell fate is primarily determined by Foxa2 with a supportive action of Lmx1a/b through repressing Nkx6.1, which inhibits FP cell differentiation. Thus, FP and mesDA identities are determined by distinct specification pathways, both of which are controlled by the same combination of transcription factors, Lmx1a/b and Foxa2, and, as a consequence, mesDA neurons are generated from mesencephalic FP cells.
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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 [80]
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- Authors
- Nakatani, T., Kumai, M., Mizuhara, E., Minaki, Y., & Ono, Y.
- Affiliations
- KAN Research Institute (JP)
- ORCID
- Minaki, Yasuko
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 339
- Issue
- 1
- Pages
- 101-113
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W1963783082
- Cited by
- 121
- References
- 37
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 14 · 2015: 12 · 2014: 8 · 2013: 16 · 2012: 13
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Directorate for Biological Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Lmx1a, Lmx1b, FOXA2, midbrain dopaminergic neurons, neuronal specification, Ngn1, NKX6.1, transcriptional repression, Parkinson's disease
- MeSH terms
- Animals, Cell Differentiation, Dopamine, Immunohistochemistry, Mesencephalon, Mice, Transgenic, Neurons, Stem Cells, Transcription Factors, Homeodomain Proteins, Cell Lineage, Mice, Hepatocyte Nuclear Factor 3-beta, LIM-Homeodomain Proteins
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