Identification of intrinsic determinants of midbrain dopamine neurons
Open accessAbstract
The prospect of using cell replacement therapies has raised the key issue of whether elucidation of developmental pathways can facilitate the generation of therapeutically important cell types from stem cells. Here we show that the homeodomain proteins Lmx1a and Msx1 function as determinants of midbrain dopamine neurons, cells that degenerate in patients with Parkinson's disease. Lmx1a is sufficient and required to trigger dopamine cell differentiation. An early activity of Lmx1a is to induce the expression of Msx1, which complements Lmx1a by inducing the proneural protein Ngn2 and neuronal differentiation. Importantly, expression of Lmx1a in embryonic stem cells results in a robust generation of dopamine neurons with a "correct" midbrain identity. These data establish that Lmx1a and Msx1 are critical intrinsic dopamine-neuron determinants in vivo and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease.
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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 [71]
Midbrain dopamine neurons originate from the mesodiencephalic floorplate, a region at the ventral midline defined by Shh+ and Foxa2+ expression.
“These neurons originate from the mesodiencephalic floorplate (FP), a region at the ventral midline defined by the mRNA expression of Shh+ and Foxa2+ [67–73].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [71]
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Self-citation
- Authors
- Andersson, E., Tryggvason, U., Deng, Q., Friling, S., Alekseenko, Z., Robert, B., Perlmann, T., & Ericson, J.
- Affiliations
- Karolinska Institutet (SE)
- Ludwig Cancer Research (SE)
- Corresponding author
- Perlmann, Thomas
- Ericson, Johan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 124
- Issue
- 2
- Pages
- 393-405
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2111525324
- Cited by
- 587
- References
- 59
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 14 · 2021: 18 · 2020: 22 · 2019: 18 · 2018: 19 · 2017: 21 · 2016: 26 · 2015: 29 · 2014: 22 · 2013: 45 · 2012: 48
- FWCI
- 22.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- midbrain dopaminergic neurons, Lmx1a, MSX1, Ngn2, homeodomain transcription factor, neuronal differentiation, Parkinson's disease, cell replacement therapy, embryonic stem cells, proneural genes
- MeSH terms
- Animals, Cells, Cultured, Chick Embryo, Dopamine, Mesencephalon, Neurons, Stem Cells, Transcription Factors, Signal Transduction, Trans-Activators, Homeodomain Proteins, Embryo Research, Mice, MSX1 Transcription Factor, Hedgehog Proteins, LIM-Homeodomain Proteins
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