Lmx1b, Pet-1, and Nkx2.2 Coordinately Specify Serotonergic Neurotransmitter Phenotype
Open accessAbstract
Serotonergic (5-HT) neurons in the brainstem modulate a wide range of physiological processes and behaviors. Two transcription factor genes,Pet-1 and Nkx2.2, are necessary but not sufficient to specify the 5-HT transmitter phenotype. Here we show that the Lim class homeobox gene Lmx1b is required for proper formation of the entire 5-HT system in the hindbrain, as indicated by the loss of expression of genes necessary for serotonin synthesis and transport in Lmx1b null mice. Lmx1b and Pet1 act downstream of Nkx2.2, and their expression is independently regulated at the time when 5-HT transmitter phenotype is specified. Ectopic expression of Lmx1b plus Pet-1 is able to induce formation of 5-HT cells in the most ventral spinal cord, where Nkx2.2 is normally expressed. Combined expression of all three genes,Lmx1b, Pet-1, and Nkx2.2, drives 5-HT differentiation in the dorsal spinal cord. Our studies therefore define a molecular pathway necessary and sufficient to specify the serotonergic neurotransmitter phenotype.
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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 [113]
The section “Lmx1b is expressed in developing serotonergic neurons” reports Lmx1b in all 5-HT neurons, supporting the clause attributed to this paper. It also reports Lmx1b-positive neurons that are 5-HT-negative, so the evidence does not support “specifically” if that means exclusive expression in serotonergic cells. The preceding co-expression clause is attached to citation 112, not this source. (LLM, conf=0.86)
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- Authors
- Cheng, L., Chen, C.-L., Luo, P., Tan, M., Qiu, M., Johnson, R., & Ma, Q.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-11-05
- Volume
- 23
- Issue
- 31
- Pages
- 9961-9967
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740868
- OpenAlex
- W1831469814
- Cited by
- 177
- References
- 44
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 5 · 2013: 8 · 2012: 9
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research (1 R01 DE13843-01, R01DE013843)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
- Keywords
- Lmx1b, Nkx2.2, serotonergic neurons, transcription factors, hindbrain development, spinal cord, serotonin synthesis, serotonin transport, gene regulatory pathways, LIM homeobox genes
- MeSH terms
- Homeobox Protein Nkx-2.2, Animals, Chick Embryo, Mice, Mutant Strains, Neurons, Phenotype, Rhombencephalon, Serotonin, Spinal Cord, Transcription Factors, In Situ Hybridization, Electroporation, Homeodomain Proteins, Gene Expression Regulation, Developmental, Zebrafish Proteins, Mice, LIM-Homeodomain Proteins
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