Lmx1a and Lmx1b Function Cooperatively to Regulate Proliferation, Specification, and Differentiation of Midbrain Dopaminergic Progenitors
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LIM homeodomain transcription factors, Lmx1a and Lmx1b, are required for the development of midbrain dopaminergic (mDA) neurons. Lmx1b is required for the specification and maintenance of mDA neurons, primarily due to its role in isthmic organizer development that is essential for the induction of mDA neurons. Here, we conditionally deleted Lmx1b in the ventral neural tube using ShhCre and found that Lmx1b conditional mutant mouse embryos show no defect in the development and maintenance of mDA neurons. In addition,Dreher(Lmx1a mutant) embryos display only a moderate reduction in the number of mDA neurons, suggesting that the related family member Lmx1b might compensate for Lmx1a function. We therefore generated Lmx1a and Lmx1b double mutants. Severe loss of mDA neurons occurred in Lmx1a dr/dr;ShhCre/+;Lmx1b f/fdouble mutants due to essential roles for Lmx1a and Lmx1b in regulating the proliferation and neuronal commitment of mDA progenitors through the expression of Wnt1 and Ngn2, respectively. Lmx1a and Lmx1b also negatively regulate Hes1 expression and consequently cell cycle exit through activation of p27 Kip1 expression. In addition, Lmx1a and Lmx1b also regulate the expression of floor plate genes such as Corin and Slit2 and specification of postmitotic mDA neurons. These defects were more severe with decreasing gene dosage of Lmx1a and Lmx1b or observed only when all four copies of Lmx1a and Lmx1b genes were inactivated. Together, our results demonstrate that Lmx1a and Lmx1b function cooperatively to regulate proliferation, specification, and differentiation of mDA progenitors, including their floor plate-like properties.
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Lmx1a and Lmx1b are co-expressed in hindbrain glutamatergic and midbrain dopaminergic cell types, and Lmx1b is also specifically expressed in serotonergic types.
“Lmx1a and Lmx1b are co-expressed in hindbrain glutamatergic and midbrain dopaminergic cell types112, and Lmx1b is also specifically expressed in serotonergic types113,114.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [112]
The Introduction says midbrain dopaminergic progenitors express both Lmx1a and Lmx1b, and the section on postmitotic mDA neurons describes precursors expressing both. Our copy does not establish their co-expression in hindbrain glutamatergic cell types. The serotonergic clause is attached to citations 113 and 114, not this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 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 [79]
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Self-citation
- Authors
- Yan, C. H., Levesque, M., Claxton, S., Johnson, R. L., & Ang, S.-L.
- Affiliations
- National Institute for Medical Research (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-08-31
- Volume
- 31
- Issue
- 35
- Pages
- 12413-12425
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6703256
- OpenAlex
- W2082347868
- Cited by
- 144
- References
- 52
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 14 · 2023: 7 · 2022: 10 · 2021: 6 · 2020: 14 · 2019: 11 · 2018: 1 · 2017: 6 · 2016: 10 · 2015: 16 · 2014: 5 · 2013: 16 · 2012: 15
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Parkinson's UK (G-0617)
- 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
- Lmx1a, Lmx1b, midbrain dopaminergic neurons, LIM-homeodomain transcription factor, isthmic organizer, neuronal specification, neuronal proliferation, neuronal differentiation, Wnt1, Ngn2, Hes1, p27, corin, Slit2, gene dosage, conditional knockout
- MeSH terms
- Animals, Animals, Newborn, Bromodeoxyuridine, Cell Count, Cell Cycle, Cell Differentiation, Dopamine, Embryo, Mammalian, Mesencephalon, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Transcription Factors, Signal Transduction, Homeodomain Proteins, Gene Expression Regulation, Developmental, Cell Proliferation, Transcription Factor Brn-3A, Mice, Hedgehog Proteins, Neurogenesis, Neural Stem Cells, LIM-Homeodomain Proteins, In Vitro Techniques
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