Directing GABAergic neuronal identity from human iPSCs through developmental patterning

  • Stem Cell Reports. 2026 Sep 24:103086. doi: 10.1016/j.stemcr.2026.103086.
Ruiqi Hu  1 ,  Linda L Boshans  1 ,  Yiran Tao  1 ,  Bohan Zhu  2 ,  Junlong Li  3 ,  Xindi Li  3 ,  Rui Dang  4 ,  Marianna Liang  5 ,  Peiwen Cai  2 ,  Mark Youssef  1 ,  Gizem Inak  1 ,  Yingnan Song  6 ,  Xuran Wang  6 ,  Alexander M Tsankov  2 ,  Joseph D Buxbaum  6 ,  Peng Jiang  4 ,  Zhiping P Pang  3 ,  Sai Ma  7 ,  Nan Yang  8
Affiliations
  • 1. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Alper Center for Neurodevelopment and Regeneration, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 2. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 3. Center for NeuroMetabolism, The Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
  • 4. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
  • 5. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Alper Center for Neurodevelopment and Regeneration, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
  • 6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
  • 8. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Alper Center for Neurodevelopment and Regeneration, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].
PMID: 42785309 DOI: 10.1016/j.stemcr.2026.103086
Abstract

GABAergic interneurons are implicated in numerous neurodevelopmental and neuropsychiatric disorders. Transcription factor (TF)-mediated induction of human pluripotent stem cells (PSCs) rapidly generates GABAergic neurons, yet their regional identity remains poorly defined. Here, we show that the chromatin state of the starting population constrains the neuronal identities specified by ASCL1 and DLX2. Brief neural patterning via dual-SMAD and Wnt inhibition prior to TF induction biases PSCs toward GABAergic neurons with forebrain-associated identities, whereas TF induction of PSCs yields neurons with broader regional signatures, including hypothalamic and thalamic programs. Benchmarking multiple approaches against a human fetal brain atlas reveals distinct regional identity biases and disease gene enrichment profiles across methods, providing a framework for selecting differentiation strategies for disease modeling. Applying this approach to ADNP syndrome, we demonstrate that the recurrent p.Tyr719∗ mutation disrupts interneuron maturation and subtype-associated transcriptional programs and impairs inhibitory synaptic transmission in human GABAergic neurons.

Keywords
GABAergic neurons; differentiation; disease modeling; human stem cells.
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