LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons
Open accessAbstract
Coordination of voluntary motor activity depends on the generation of the appropriate neuronal subtypes in the basal ganglia and their integration into functional neuronal circuits. The largest nucleus of the basal ganglia, the striatum, contains two classes of neurons: the principal population of medium-sized dense spiny neurons (MSNs; 97-98% of all striatal neurons in rodents), which project to the globus pallidus and the substantia nigra, and the locally projecting striatal interneurons (SINs; 2-3% in rodents). SINs are further subdivided into two non-overlapping groups: those producing acetylcholine (cholinergic) and those producing γ-amino butyric acid(GABAergic). Despite the pivotal role of SINs in integrating the output of striatal circuits and the function of neuronal networks in the ventral forebrain, the lineage relationship of SIN subtypes and the molecular mechanisms that control their differentiation are currently unclear. Using genetic fate mapping, we demonstrate here that the majority of cholinergic and GABAergic SINs are derived from common precursors generated in the medial ganglionic eminence during embryogenesis. These precursors express the LIM homeodomain protein Lhx6 and have characteristics of proto-GABAergic neurons. By combining gene expression analysis with loss-of-function and misexpression experiments, we provide evidence that the differentiation of the common precursor into mature SIN subtypes is regulated by the combinatorial activity of the LIM homeodomain proteins Lhx6, Lhx7 (Lhx8) and Isl1. These studies suggest that a LIM homeodomain transcriptional code confers cell-fate specification and neurotransmitter identity in neuronal subpopulations of the ventral forebrain.
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Lhx6 and Lhx8 are co-expressed in some CNU and hypothalamus GABAergic types, but Lhx6 is also specifically expressed in MGE types.
“Lhx6 and Lhx8 are co-expressed in some CNU and hypothalamus GABAergic types110,111, but Lhx6 is also specifically expressed in MGE types.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [111]
The Results (page unavailable) show Lhx6 in a subset of Lhx7-reporter-positive striatal cells; the Introduction identifies Lhx7 as Lhx8. The Discussion (page unavailable) reports Lhx7-reporter expression in hypothalamic GABAergic neurons, but does not establish that those neurons also express Lhx6. (LLM, conf=0.86)
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- Authors
- Fragkouli, A., van Wijk, N. V., Lopes, R., Kessaris, N., & Pachnis, V.
- Affiliations
- National Institute for Medical Research (GB)
- Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
- University College London (GB)
- Corresponding author
- Pachnis, Vassilis
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2009-11-15
- Volume
- 136
- Issue
- 22
- Pages
- 3841-3851
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC2766344
- OpenAlex
- W2043681554
- Cited by
- 135
- References
- 61
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 14 · 2020: 4 · 2019: 9 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 8 · 2014: 11 · 2013: 17 · 2012: 4
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- European Commission
- Medical Research Council
- 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
- striatal interneurons, cholinergic neurons, GABAergic neurons, medial ganglionic eminence, Lhx6, Lhx8, Isl1, LIM-homeodomain transcription factor, neuronal fate specification, neurotransmitter identity, basal ganglia, ventral forebrain, medium spiny neurons, genetic fate mapping
- MeSH terms
- Animals, Embryo, Mammalian, Ganglia, Interneurons, Prosencephalon, Homeodomain Proteins, Mice
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