Generation of pure GABAergic neurons by transcription factor programming
Open accessAbstract
Approaches to differentiating pluripotent stem cells (PSCs) into neurons currently face two major challenges-(i) generated cells are immature, with limited functional properties; and (ii) cultures exhibit heterogeneous neuronal subtypes and maturation stages. Using lineage-determining transcription factors, we previously developed a single-step method to generate glutamatergic neurons from human PSCs. Here, we show that transient expression of the transcription factors Ascl1 and Dlx2 (AD) induces the generation of exclusively GABAergic neurons from human PSCs with a high degree of synaptic maturation. These AD-induced neuronal (iN) cells represent largely nonoverlapping populations of GABAergic neurons that express various subtype-specific markers. We further used AD-iN cells to establish that human collybistin, the loss of gene function of which causes severe encephalopathy, is required for inhibitory synaptic function. The generation of defined populations of functionally mature human GABAergic neurons represents an important step toward enabling the study of diseases affecting inhibitory synaptic transmission.
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Induced expression of different transcription factors yields other neuron types, such as motor neurons and inhibitory neurons.
“induced expression of different transcription factors yield other types of neurons, such as motor neurons (Hester et al., 2011; Shi et al., 2018) and inhibitory neurons (Yang et al., 2017).”
From CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons (2019) · cites this paper as Yang et al., 2017
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- Authors
- Yang, N., Chanda, S., Marro, S., Ng, Y.-H., Janas, J. A., Haag, D., Ang, C. E., Tang, Y., Flores, Q., Mall, M., Wapinski, O., Li, M., Ahlenius, H., Rubenstein, J. L., Chang, H. Y., Buylla, A. A., Südhof, T. C., & Wernig, M.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Corresponding author
- Wernig, Marius
- ORCID
- Venue
- Nature Methods
- Published
- 2017-05-15
- Volume
- 14
- Issue
- 6
- Pages
- 621-628
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC5567689
- OpenAlex
- W2613062475
- Cited by
- 341
- References
- 42
- Citations by year
- 2026: 21 · 2025: 42 · 2024: 28 · 2023: 41 · 2022: 44 · 2021: 51 · 2020: 48 · 2019: 34 · 2018: 23 · 2017: 5 · 2016: 1 · 2014: 1
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH092931, U19MH104172, R01MH049428, R37MH049428)
- National Human Genome Research Institute (P50HG007735)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R37HD032116, R01HD032116)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GABAergic neurons, ASCL1, Dlx2, human pluripotent stem cells, neuronal differentiation, synapse maturation, collybistin, synaptic inhibition, disease modeling
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Humans, Transcription Factors, Homeodomain Proteins, Pluripotent Stem Cells, Mice, Basic Helix-Loop-Helix Proteins, GABAergic Neurons, Cell Engineering
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