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Cited by 118Pluripotent Stem Cells ResearchNeurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene Regulation

Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells

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Xue, Yuanchao, Qian, Hao, Hu, Jing, Zhou, Bing, Zhou, Yu, Hu, Xihao, Karakhanyan, Aziz, Pang, Zhiping +1 more·2016·Nature Neuroscience
DOI 10.1038/nn.4297PMC PMC4882254
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Abstract

Direct conversion of somatic cells into neurons holds great promise for regenerative medicine. However, neuronal conversion is relatively inefficient in human cells compared to mouse cells. It has been unclear what might be the key barriers to reprogramming in human cells. We recently elucidated an RNA program mediated by the polypyrimidine tract binding protein PTB to convert mouse embryonic fibroblasts (MEFs) into functional neurons. In human adult fibroblasts (HAFs), however, we unexpectedly found that invoking the documented PTB-REST-miR-124 loop generates only immature neurons. We now report that the functionality requires sequential inactivation of PTB and the PTB paralog nPTB in HAFs. Inactivation of nPTB triggers another self-enforcing loop essential for neuronal maturation, which comprises nPTB, the transcription factor BRN2, and miR-9. These findings suggest that two separate gatekeepers control neuronal conversion and maturation and consecutively overcoming these gatekeepers enables deterministic reprogramming of HAFs into functional neurons.

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  • PTBP1 depletion has also been linked to broader neurogenic regulatory circuits, including the miR-124/REST pathway involved in neuronal induction and the PTBP2/miR-9/BRN2 axis implicated in neuronal maturation.

    “PTBP1 depletion has also been linked to broader neurogenic regulatory circuits, including the miR-124/REST pathway involved in neuronal induction and the PTBP2/miR-9/BRN2 axis implicated in neuronal maturation.”

    From Reverse the progression of Alzheimer’s disease through Nano-ERASER-based adult neuroregeneration (2026) · cites this paper as [26]

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Authors
Xue, Y., Qian, H., Hu, J., Zhou, B., Zhou, Y., Hu, X., Karakhanyan, A., Pang, Z., & Fu, X.-D.
Affiliations
  • Chinese Academy of Sciences (CN)
  • University of California San Diego (US)
  • Rutgers, The State University of New Jersey (US)
Corresponding author
  • Xue, Yuanchao
  • Fu, Xiang-Dong
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2016-04-25
Volume
19
Issue
6
Pages
807-815
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4297
PMC
PMC4882254
OpenAlex
W2344675989
Cited by
118
References
10
Citations by year
2026: 10 · 2025: 6 · 2024: 9 · 2023: 14 · 2022: 13 · 2021: 16 · 2020: 17 · 2019: 9 · 2018: 11 · 2017: 12 · 2016: 1
FWCI
5.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Human Genome Research Institute (R01HG004659)
  • National Cancer Institute (P30CA023100)
  • National Institute of General Medical Sciences (R01GM049369)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
neuronal reprogramming, PTB, polypyrimidine tract-binding protein, miR-124, rest, miR-9, Brn2, neuronal maturation, neurogenesis, RNA-binding proteins
MeSH terms
Cell Line, Fibroblasts, Humans, Nerve Tissue Proteins, Neurons, Alternative Splicing, Polypyrimidine Tract-Binding Protein, Neural Stem Cells, Cellular Reprogramming

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