LIM Homeobox 8 (Lhx8) Is a Key Regulator of the Cholinergic Neuronal Function via a Tropomyosin Receptor Kinase A (TrkA)-mediated Positive Feedback Loop
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Basal forebrain cholinergic neurons play an important role in cognitive functions such as learning and memory, and they are affected in several neurodegenerative diseases, including Alzheimer disease and Down syndrome. Despite their functional importance, the molecular mechanisms of functional maturation and maintenance of these cholinergic neurons after the differentiation stage have not been fully elucidated. This study demonstrates that the LIM homeobox 8 (Lhx8) transcription factor regulates cholinergic function in rat septal cholinergic neurons in primary cultures from E18.5 embryos and in the adult brain. Lhx8 expression modulated tropomyosin receptor kinase A (TrkA) expression in septal cholinergic neurons in vitro and in vivo, resulting in regulated acetylcholine release as an index of cholinergic function. In addition, Lhx8 expression and function were regulated by nerve growth factor (NGF), and the effect of NGF was potentiated by Lhx8-induced TrkA expression. Together, our findings suggest that positive feedback regulation between Lhx8, TrkA, and NGF is an important regulatory mechanism for cholinergic functions of the septum.
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Lhx8 expression induces vesicular ACh transporter activity and acetylcholine release.
“Lhx8 expression also induces Vesicular ACh transporter activity and acetylcholine release [54,55].”
From Rapid changes in plasma corticosterone and medial amygdala transcriptome profiles during social status change reveal molecular pathways associated with a major life history transition in mouse dominance hierarchies (2025) · cites this paper as [55]
The Results section reports that Lhx8 overexpression increased acetylcholine release from cultured rat medial septal neurons. The Discussion mentions increased vesicular acetylcholine transporter expression as an effect of NGF, but does not show that Lhx8 induces the transporter's activity. Page numbers are unavailable in our copy. (LLM, conf=0.90)
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Developmental specification of forebrain cholinergic neurons
Allaway, K. C., & Machold, R. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2016.11.007 · Cited by 68 · see citing works
Milewski, T. M., Lee, W., Young, R. L., Hofmann, H. A., & Curley, J. P. (2025) · PLoS Genetics · doi:10.1371/journal.pgen.1011548 · Cited by 7 · see citing works
- Authors
- Tomioka, T., Shimazaki, T., Yamauchi, T., Oki, T., Ohgoh, M., & Okano, H.
- Affiliations
- Keio University (JP)
- Eisai (Japan) (JP)
- Corresponding author
- Okano, Hideyuki
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 289
- Issue
- 2
- Pages
- 1000-1010
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3887170
- OpenAlex
- W2007168534
- Cited by
- 27
- References
- 2
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 2 · 2019: 1 · 2016: 1
- FWCI
- 0.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Lhx8, TrkA, nerve growth factor, septal cholinergic neurons, basal forebrain cholinergic neurons, acetylcholine release, positive feedback loop, transcriptional regulation, Alzheimer's disease, Down syndrome, neuronal maturation
- MeSH terms
- Acetylcholine, Animals, Cells, Cultured, Humans, Immunohistochemistry, Male, Transcription Factors, Blotting, Western, Gene Expression, PC12 Cells, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Receptor, trkA, Nerve Growth Factor, Feedback, Physiological, Rats, HEK293 Cells, Cholinergic Neurons, LIM-Homeodomain Proteins
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