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Over-Expression of Cyclin D1 Promotes NSCs Proliferation and Induces the Differentiation into Astrocytes Via Jak-STAT3 Pathways

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Abstract

Precise control of the proliferation and differentiation of multipotent neural stem cells (NSCs) is crucial for the proper development of the nervous system. Although cyclinD1 has been implicated as a cause of cancer in many studies, its roles in NSCs remain elusive. In this study, we examined the over-expression of cyclinD1 in controlling the self-renewal and differentiation of NSCs. Moreover, we found that the over-expression of cyclinD1 can drive cells to enter S phase and support the clonal self-renewing growth of NSCs. During the differentiation of NSCs, the over-expression of cyclinD1 promoted the generation of astrocytes, and their promotion likely occurred through synergistic phosphorylation of the signal transducer and activator of transcription 3. Our data suggest that the over-expression of cyclinD1 promotes the proliferation of NSCs and induces their differentiation into astrocytes via Jak-STAT3 pathways.

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References

  1. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829–834

    Article  CAS  PubMed  Google Scholar 

  2. Sauvageot CM, Stiles CD (2002) Molecular mechanisms controlling cortical gliogenesis. Curr Opin Neurobiol 12:244–249

    Article  CAS  PubMed  Google Scholar 

  3. Bramanti V, Campisi A, Tomassoni D, Li Volti G, Caccamo D et al (2008) Effect of acetylcholine precursors on proliferation and differentiation of astroglial cells in primary cultures. Neurochem Res 33:2601–2608

    Article  CAS  PubMed  Google Scholar 

  4. Bramanti V, Grasso S, Tomassoni D, Traini E, Raciti G et al (2015) Effect of growth factors and steroid hormones on heme oxygenase and cyclin D1 expression in primary astroglial cell cultures. J Neurosci Res 93:521–529

    Article  CAS  PubMed  Google Scholar 

  5. Bramanti V, Tomassoni D, Bronzi D, Grasso S, Curro M et al (2010) Alpha-lipoic acid modulates GFAP, vimentin, nestin, cyclin D1 and MAP-kinase expression in astroglial cell cultures. Neurochem Res 35:2070–2077

    Article  CAS  PubMed  Google Scholar 

  6. Swanton C (2004) Cell-cycle targeted therapies. Lancet Oncol 5:27–36

    Article  CAS  PubMed  Google Scholar 

  7. Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV et al (2003) A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114:323–334

    Article  CAS  PubMed  Google Scholar 

  8. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11:558–572

    Article  CAS  PubMed  Google Scholar 

  9. Hayes TE, Valtz NL, McKay RD (1991) Downregulation of CDC2 upon terminal differentiation of neurons. New Biol 3:259–269

    CAS  PubMed  Google Scholar 

  10. Okano HJ, Pfaff DW, Gibbs RB (1993) RB and Cdc2 expression in brain: correlations with 3H-thymidine incorporation and neurogenesis. J Neurosci 13:2930–2938

    CAS  PubMed  Google Scholar 

  11. John PC, Mews M, Moore R (2001) Cyclin/Cdk complexes: their involvement in cell cycle progression and mitotic division. Protoplasma 216:119–142

    Article  CAS  PubMed  Google Scholar 

  12. White J, Dalton S (2005) Cell cycle control of embryonic stem cells. Stem Cell Rev 1:131–138

    Article  CAS  PubMed  Google Scholar 

  13. Yan GZ, Ziff EB (1995) NGF regulates the PC12 cell cycle machinery through specific inhibition of the Cdk kinases and induction of cyclin D1. J Neurosci 15:6200–6212

    CAS  PubMed  Google Scholar 

  14. Xiong W, Pestell R, Rosner MR (1997) Role of cyclins in neuronal differentiation of immortalized hippocampal cells. Mol Cell Biol 17:6585–6597

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Lange C, Calegari F (2010) Cdks and cyclins link G1 length and differentiation of embryonic, neural and hematopoietic stem cells. Cell Cycle 9:1893–1900

    Article  CAS  PubMed  Google Scholar 

  16. Sumrejkanchanakij P, Tamamori-Adachi M, Matsunaga Y, Eto K, Ikeda MA (2003) Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. Oncogene 22:8723–8730

    Article  CAS  PubMed  Google Scholar 

  17. Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci 23:2557–2563

    CAS  PubMed  Google Scholar 

  18. He F, Ge W, Martinowich K, Becker-Catania S, Coskun V et al (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8:616–625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA et al (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483

    Article  CAS  PubMed  Google Scholar 

  20. Nakashima K, Taga T (2002) Mechanisms underlying cytokine-mediated cell-fate regulation in the nervous system. Mol Neurobiol 25:233–244

    Article  CAS  PubMed  Google Scholar 

  21. Cao F, Hata R, Zhu P, Nakashiro K, Sakanaka M (2010) Conditional deletion of Stat3 promotes neurogenesis and inhibits astrogliogenesis in neural stem cells. Biochem Biophys Res Commun 394:843–847

    Article  CAS  PubMed  Google Scholar 

  22. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R et al (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826

    Article  CAS  PubMed  Google Scholar 

  23. Barnabe-Heider F, Wasylnka JA, Fernandes KJ, Porsche C, Sendtner M et al (2005) Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48:253–265

    Article  CAS  PubMed  Google Scholar 

  24. Yoshimatsu T, Kawaguchi D, Oishi K, Takeda K, Akira S et al (2006) Non-cell-autonomous action of STAT3 in maintenance of neural precursor cells in the mouse neocortex. Development 133:2553–2563

    Article  CAS  PubMed  Google Scholar 

  25. Nicolas CS, Amici M, Bortolotto ZA, Doherty A, Csaba Z et al (2013) The role of JAK-STAT signaling within the CNS. JAKSTAT 2:e22925

    PubMed Central  PubMed  Google Scholar 

  26. Jebbett NJ, Hamilton JW, Rand MD, Eckenstein F (2013) Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells. Neurotoxicology 38:91–100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ma J, Yu Z, Qu W, Tang Y, Zhan Y et al (2010) Proliferation and differentiation of neural stem cells are selectively regulated by knockout of cyclin D1. J Mol Neurosci 42:35–43

    Article  CAS  PubMed  Google Scholar 

  28. Kuwabara T, Hsieh J, Nakashima K, Taira K, Gage FH (2004) A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116:779–793

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Dong C (2009) Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ 16:386–394

    Article  CAS  PubMed  Google Scholar 

  30. Xiong Y, Zhang H, Beach D (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71:505–514

    Article  CAS  PubMed  Google Scholar 

  31. Pines J (2006) Mitosis: a matter of getting rid of the right protein at the right time. Trends Cell Biol 16:55–63

    Article  CAS  PubMed  Google Scholar 

  32. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821

    Article  CAS  PubMed  Google Scholar 

  33. Lukas J, Pagano M, Staskova Z, Draetta G, Bartek J (1994) Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumour cell lines. Oncogene 9:707–718

    CAS  PubMed  Google Scholar 

  34. Lange C, Huttner WB, Calegari F (2009) Cdk4/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell 5:320–331

    Article  CAS  PubMed  Google Scholar 

  35. Hardwick LJ, Ali FR, Azzarelli R, Philpott A (2015) A Cell cycle regulation of proliferation versus differentiation in the central nervous system. Cell Tissue Res 359:187–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Lukaszewicz AI, Anderson DJ (2011) Cyclin D1 promotes neurogenesis in the developing spinal cord in a cell cycle-independent manner. Proc Natl Acad Sci USA 108:11632–11637

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K et al (2010) Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463:374–378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Ferguson KL, Slack RS (2001) The Rb pathway in neurogenesis. NeuroReport 12:A55–A62

    Article  CAS  PubMed  Google Scholar 

  39. Ohori Y, Yamamoto S, Nagao M, Sugimori M, Yamamoto N et al (2006) Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J Neurosci 26:11948–11960

    Article  CAS  PubMed  Google Scholar 

  40. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T et al (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284:479–482

    Article  CAS  PubMed  Google Scholar 

  41. Bizen N, Inoue T, Shimizu T, Tabu K, Kagawa T et al (2014) A growth-promoting signaling component cyclin D1 in neural stem cells has antiastrogliogenic function to execute self-renewal. Stem Cells 32:1602–1615

    Article  CAS  PubMed  Google Scholar 

  42. Qian X, Shen Q, Goderie SK, He W, Capela A et al (2000) Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28:69–80

    Article  CAS  PubMed  Google Scholar 

  43. Tropepe V, Sibilia M, Ciruna BG, Rossant J, Wagner EF et al (1999) Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208:166–188

    Article  CAS  PubMed  Google Scholar 

  44. Lillien L, Raphael H (2000) BMP and FGF regulate the development of EGF-responsive neural progenitor cells. Development 127:4993–5005

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant from the Program of National Natural Science Foundation of China (No. 81100876) and National Postdoctoral Science Foundation of China (No. 2014M560910) and Postdoctoral Science Foundation of Chinese Academy of Medical Science (No. 2014M1330).

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Authors and Affiliations

  1. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China

    Junfang Ma, Bo Cui & Liying Cui

  2. Neuroscience Center, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China

    Liying Cui

  3. Department of Neurology, Anhui Province Hospital, Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Junfang Ma & Xiaoling Ding

  4. Research Center for Stem Cells and Developmental Biology, Department of Histology and Embryology, Xuzhou Medical College, Xuzhou, Jiangsu, People’s Republic of China

    Jianfeng Wei

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  1. Junfang Ma
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Correspondence to Liying Cui.

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Ma, J., Cui, B., Ding, X. et al. Over-Expression of Cyclin D1 Promotes NSCs Proliferation and Induces the Differentiation into Astrocytes Via Jak-STAT3 Pathways. Neurochem Res 40, 1681–1690 (2015). https://doi.org/10.1007/s11064-015-1635-9

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