Cellular and Molecular Neurobiology

, Volume 34, Issue 6, pp 881–893 | Cite as

Regulatory Role of the JNK-STAT1/3 Signaling in Neuronal Differentiation of Cultured Mouse Embryonic Stem Cells

  • Zheng Zachory Wei
  • Shan Ping Yu
  • Jin Hwan Lee
  • Dongdong Chen
  • Tammi M. Taylor
  • Todd Carter Deveau
  • Albert Cheung Hoi Yu
  • Ling WeiEmail author
Original Research


Stem cell transplantation therapy has provided promising hope for the treatment of a variety of neurodegenerative disorders. Among challenges in developing disease-specific stem cell therapies, identification of key regulatory signals for neuronal differentiation is an essential and critical issue that remains to be resolved. Several lines of evidence suggest that JNK, also known as SAPK, is involved in neuronal differentiation and neural plasticity. It may also play a role in neurite outgrowth during neuronal development. In cultured mouse embryonic stem (ES) cells, we test the hypothesis that the JNK pathway is required for neuronal differentiation. After neural induction, the cells were plated and underwent differentiation for up to 5 days. Western blot analysis showed a dramatic increase in phosphorylated JNKs at 1–5 days after plating. The phosphorylation of JNK subsequently induced activation of STAT1 and STAT3 that lead to expressions of GAP-43, neurofilament, βIII-tubulin, and synaptophysin. NeuN-colabelled with DCX, a marker for neuroblast, was enhanced by JNK signaling. Neuronal differentiation of ES cells was attenuated by treatment with SP600125, which inhibited the JNK activation and decreased the activation of STAT1 and STAT3, and consequently suppressed the expressions of GAP-43, neurofilament, βIII-tubulin, and the secretion of VEGF. Data from immunocytochemistry indicated that the nuclear translocation of STAT3 was reduced, and neurites of ES-derived neurons were shorter after treatment with SP600125 compared with control cells. These results suggest that the JNK-STAT3 pathway is a key regulator required for early neuronal differentiation of mouse ES cells. Further investigation on expression of JNK isoforms showed that JNK-3 was significantly upregulated during the differentiation stage, while JNK-1 and JNK-2 levels decreased. Our study provided interesting information on JNK functions during ES cell neuronal differentiation.


Embryonic stem cell JNK STAT3 Neurite outgrowth Neuronal differentiation 



This work was supported by grants from the National Institutes of Health, USA (NS045810 to SPY, NS057255 and NS075338 to LW), the American Heart Association Established Investigator Award (0840110N to LW), a Grant-in-Aid award (12GRNT12060222 to SPY) and a VA national merit grant (SPY). This work was also supported by the NIH grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.

Conflict of interest

All authors have no conflict of interest in this investigation.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zheng Zachory Wei
    • 1
    • 2
  • Shan Ping Yu
    • 1
    • 2
  • Jin Hwan Lee
    • 1
  • Dongdong Chen
    • 1
    • 2
  • Tammi M. Taylor
    • 1
  • Todd Carter Deveau
    • 1
  • Albert Cheung Hoi Yu
    • 3
  • Ling Wei
    • 1
    • 4
    Email author
  1. 1.Department of AnesthesiologyEmory University School of MedicineAtlantaUSA
  2. 2.Center for Visual and Neurocognitive RehabilitationAtlanta VA Medical CenterDecaturUSA
  3. 3.Neuroscience Research Institute and Department of NeurobiologyPeking University School of Basic Medical SciencesBeijingChina
  4. 4.Department of NeurologyEmory University School of MedicineAtlantaUSA

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