ArticlePLoS genetics2014
Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 119 citations in OpenAlex.
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- Regulatory logic of neuronal differentiation in theProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Gestational Hypoxia Disrupts Medial Ganglionic Eminence Progenitor Dynamics and Interneuron Development in Schizophrenia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Regulatory logic of neuronal identity specification inbioRxiv : the preprint server for biology · 2025Article
- An integrated transcriptomic approach for identifying enhancers in limb motor pools.Scientific reports · 2025Article
- Impact of Neuroimmune System Activation by Adolescent Binge Alcohol Exposure on Adult Neurobiology.Advances in experimental medicine and biology · 2025Review
- Regulation of neuronal fate specification and connectivity of the thalamic reticular nucleus by the Ascl1-Isl1 transcriptional cascade.Cellular and molecular life sciences : CMLS · 2024Article
- Molecular and Cellular Mechanisms of Motor Circuit Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Understanding the Role of the SMN Complex Component GEMIN5 and Its Functional Relationship with Demethylase KDM6B in the Flunarizine-Mediated Neuroprotection of Motor Neuron Disease Spinal Muscular Atrophy.International journal of molecular sciences · 2024Article
- UNC-30/PITX coordinates neurotransmitter identity with postsynaptic GABA receptor clustering.Development (Cambridge, England) · 2024Article
- Acetylcholine Neurons Become Cholinergic during Three Time Windows in the Developing Mouse Brain.eNeuro · 2024Article
- Maintenance of neuronal identity in C. elegans and beyond: Lessons from transcription and chromatin factors.Seminars in cell & developmental biology · 2024Review
- HMGB1 neuroimmune signaling and REST-G9a gene repression contribute to ethanol-induced reversible suppression of the cholinergic neuron phenotype.Molecular psychiatry · 2023Article
- Spatiotemporal Regulation ofeNeuro · 2023Article
- Basal forebrain cholinergic signalling: development, connectivity and roles in cognition.Nature reviews. Neuroscience · 2023Review
- Loss ofFrontiers in neuroscience · 2023Article
- Review
- Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism.Nature communications · 2022Article
- Ontogenetic rules for the molecular diversification of hypothalamic neurons.Nature reviews. Neuroscience · 2022Review
- A conserved transcriptional fingerprint of multi-neurotransmitter neurons necessary for social behavior.BMC genomics · 2022Article
14 more citing papers are in PubMed but not listed here.
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11 authors at 4 institutions in 2 countries.
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Abstract
The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). Conditional inactivation of Isl1, a LIM homeodomain factor expressed in both differentiating MNs and FCNs, led to a drastic loss of cholinergic neurons in the developing spinal cord and forebrain. We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Consistently, the Isl1-Lhx3-hexamer directly coordinated upregulation of cholinergic pathways genes in embryonic spinal cord. Similarly, in the developing forebrain, the Isl1-Lhx8-hexamer was recruited to the cholinergic gene battery and promoted cholinergic gene expression. Furthermore, the expression of the Isl1-Lhx8-complex enabled the acquisition of cholinergic fate in embryonic stem cell-derived neurons. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover an important gene regulatory mechanism that directs a specific neurotransmitter identity in vertebrate CNS development.
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