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Induction of specific neuron types by overexpression of single transcription factors

  • Yusuke Teratani-Ota
  • Kohei Yamamizu
  • Yulan Piao
  • Lioudmila Sharova
  • Misa Amano
  • Hong Yu
  • David Schlessinger
  • Minoru S. H. Ko
  • Alexei A. Sharov
Article

Summary

Specific neuronal types derived from embryonic stem cells (ESCs) can facilitate mechanistic studies and potentially aid in regenerative medicine. Existing induction methods, however, mostly rely on the effects of the combined action of multiple added growth factors, which generally tend to result in mixed populations of neurons. Here, we report that overexpression of specific transcription factors (TFs) in ESCs can rather guide the differentiation of ESCs towards specific neuron lineages. Analysis of data on gene expression changes 2 d after induction of each of 185 TFs implicated candidate TFs for further ESC differentiation studies. Induction of 23 TFs (out of 49 TFs tested) for 6 d facilitated neural differentiation of ESCs as inferred from increased proportion of cells with neural progenitor marker PSA-NCAM. We identified early activation of the Notch signaling pathway as a common feature of most potent inducers of neural differentiation. The majority of neuron-like cells generated by induction of Ascl1, Smad7, Nr2f1, Dlx2, Dlx4, Nr2f2, Barhl2, and Lhx1 were GABA-positive and expressed other markers of GABAergic neurons. In the same way, we identified Lmx1a and Nr4a2 as inducers for neurons bearing dopaminergic markers and Isl1, Fezf2, and St18 for cholinergic motor neurons. A time-course experiment with induction of Ascl1 showed early upregulation of most neural-specific messenger RNA (mRNA) and microRNAs (miRNAs). Sets of Ascl1-induced mRNAs and miRNAs were enriched in Ascl1 targets. In further studies, enrichment of cells obtained with the induction of Ascl1, Smad7, and Nr2f1 using microbeads resulted in essentially pure population of neuron-like cells with expression profiles similar to neural tissues and expressed markers of GABAergic neurons. In summary, this study indicates that induction of transcription factors is a promising approach to generate cultures that show the transcription profiles characteristic of specific neural cell types.

Keywords

GABAergic neurons Dopaminergic neurons Cholinergic neurons Ascl1 ESCs Gene expression profiling miRNA 

Notes

Acknowledgments

This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, project Z01 AG000656-09. Y.T-O. was funded by Post-Baccalaureate Intramural Research Training Award. K.Y. was supported by the postdoctoral fellowships from the Kanae Foundation, Japan, Uehara Memorial Foundation, Japan, Naito Foundation, Japan, and the Japan Society for Promotion of Science (JSPS). This research was also supported in part by the Japan Science and Technology Agency (JST), CREST program. The authors declare no competing financial interests. Y.T-O., K.Y., Y.P., and L.S. performed experiments; M.A. made new ES clones; H.Y. carried out vector construction for ES clones and synthetic mRNA; D.S. and M.S.H.K supervised the project and edited the manuscript; and A.A.S. performed statistical analysis and wrote the manuscript.

Supplementary material

11626_2016_56_MOESM1_ESM.doc (8.8 mb)
ESM 1 (DOC 9011 kb)

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Copyright information

© The Society for In Vitro Biology 2016

Authors and Affiliations

  • Yusuke Teratani-Ota
    • 1
    • 2
  • Kohei Yamamizu
    • 1
    • 3
  • Yulan Piao
    • 1
  • Lioudmila Sharova
    • 1
  • Misa Amano
    • 1
    • 4
  • Hong Yu
    • 1
    • 4
  • David Schlessinger
    • 1
  • Minoru S. H. Ko
    • 5
  • Alexei A. Sharov
    • 1
  1. 1.Laboratory of Genetics, National Institute on AgingNational Institutes of HealthBaltimoreUSA
  2. 2.Department of Psychology, Center for NeuroscienceUC DavisDavisUSA
  3. 3.Laboratory of Stem Cell Differentiation, Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
  4. 4.Elixirgen, LLCBaltimoreUSA
  5. 5.Department of Systems Medicine, Sakaguchi LaboratoryKeio University School of MedicineTokyoJapan

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