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The Regulatory Mechanism of Neurogenesis by IGF-1 in Adult Mice

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Abstract

Growth factors like insulin-like growth factor 1 (IGF-1) is reported to mediate neurogenesis in the subgranular zone (SGZ) and the subventricular zone (SVZ) of the adult mammalian brain, but its regulatory mechanism remains unclear. We generated transgenic mice overexpressing IGF-1 specifically in neural stem cells (NSCs) and assessed the effect of IGF-1 on neurogenesis in adult mice NSCs. Overexpression of IGF-1 could stimulate the expression of phospho-Akt and phospho-ERK1/2 while inducing proliferation and differentiation of NSCs in the SGZ and SVZ. The MEK/ERK inhibitor U0126 could inhibit ERK1/2 phosphorylation, further inhibiting the proliferation of NSCs in the SGZ and SVZ but had no effect on the phosphorylation of Akt. By contrast, The PI3K/Akt inhibitor LY294002 inhibited phosphorylation of Akt and differentiation of NSCs in the SGZ and SVZ, resulting in no change in the proliferation of NSCs and ERK1/2 phosphorylation. These results demonstrate that IGF-1 upregulates the proliferation of NSCs by triggering MEK/ERK pathway signaling in the adult mice SGZ and SVZ. Meanwhile, IGF-1 also induces differentiation of NSCs via the PI3K/Akt pathway in adult mice. However, we found no evidence of crosstalk between the PI3K/Akt and MEK/ERK pathways in adult mice NSCs. Our work provides new experimental evidence of the involvement of the PI3K/Akt and MEK/ERK pathways in the proliferation and differentiation of the NSCs of adult mice.

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References

  1. Chiasson BJ, Tropepe V, Morshead CM, van der Kooy D (1999) Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci 19:4462–4471

    CAS  PubMed  Google Scholar 

  2. Loeffler M, Roeder I (2002) Tissue stem cells: definition, plasticity, heterogeneity, self-organization and models e a conceptual approach. Cells Tissues Organs 171:8–26

    Article  PubMed  Google Scholar 

  3. Duman RS, Malberg J, Nakagawa S (2001) Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther 299:401–407

    CAS  PubMed  Google Scholar 

  4. Fuchs E, Gould E (2000) Mini-review: in vivo neurogenesis in the adult brain: regulation and functional implications. Eur J Neurosci 12:2211–2214

    Article  CAS  PubMed  Google Scholar 

  5. Kempermann G (2002) Regulation of adult hippocampal neurogenesis implications for novel theories of major depression. Bipolar Disord 4:17–33

    Article  PubMed  Google Scholar 

  6. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

    Article  CAS  PubMed  Google Scholar 

  7. Peng H, Whitney N, Wu Y, Tian C, Dou H, Zhou Y, Zheng J (2008) HIV-1-infected and/or immune-activated macrophage-secreted TNF-alpha affects human fetal cortical neural progenitor cell proliferation and differentiation. Glia 56:903–916

    Article  PubMed Central  PubMed  Google Scholar 

  8. Grote HE, Hannan AJ (2007) Regulators of adult neurogenesis in the healthy and diseased brain. Clin Exp Pharmacol Physiol 34:533–545

    Article  CAS  PubMed  Google Scholar 

  9. Gago N, Avellana-Adalid V, Evercooren AB, Schumacher M (2003) Control of cell survival and proliferation of postnatal PSA-NCAM(+) progenitors. Mol Cell Neurosci 22:162–178

    Article  CAS  PubMed  Google Scholar 

  10. Zygar CA, Colbert S, Yang D, Fernald RD (2005) IGF-1 produced by cone photoreceptors regulates rod progenitor proliferation in the teleost retina. Brain Res Dev Brain Res 154:91–100

    Article  CAS  PubMed  Google Scholar 

  11. Kouroupi G, Lavdas AA, Gaitanou M, Thomaidou D, Stylianopoulou F, Matsas R (2010) Lentivirus-mediated expression of insulin-like growth factor-1 promotes neural stem/precursor proliferation and enhances their potential to generate neurons. J Neurochem 115:460–474

    Article  CAS  PubMed  Google Scholar 

  12. Isakoff SJ, Yu YP, Su YC, Blaikie P, Yajnik V, Rose E, Weidner KM, Sachs M, Margolis B, Skolnik EY (1996) Interaction between the phosphotyrosine binding domain of Shc and the insulin receptor is required for Shc phosphorylation by insulin in vivo. J Biol Chem 271:3959–3962

    Article  CAS  PubMed  Google Scholar 

  13. Clemmons DR, Maile LA (2003) Minireview: integral membrane proteins that function coordinately with the insulin-like growth factor I receptor to regulate intracellular signaling. Endocrinology 144:1664–1670

    Article  CAS  PubMed  Google Scholar 

  14. Dupont J, Pierre A, Froment P, Moreau C (2003) The insulin-like growth factor axis in cell cycle progression. Horm Metab Res 35:740–750

    Article  CAS  PubMed  Google Scholar 

  15. Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602

    Article  CAS  PubMed  Google Scholar 

  16. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN (1995) The protein kinase encoded by the Akt protooncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81:727–736

    Article  CAS  PubMed  Google Scholar 

  17. Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10:262–267

    Article  CAS  PubMed  Google Scholar 

  18. Supeno NE, Pati S, Hadi RA, Ghani AR, Mustafa Z, Abdullah JM, Idris FM, Han X, Jaafar H (2013) IGF-1 acts as controlling switch for long-term proliferation and maintenance of EGF/FGF-responsive striatal neural stem cells. Int J Med Sci 10:522–531

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Choi YS, Cho HY, Hoyt KR, Naegele JR, Obrietan K (2008) IGF-1 Receptor-mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus. GLIA 56:791–800

    Article  PubMed Central  PubMed  Google Scholar 

  20. Kalluri HS, Vemuganti R, Dempsey RJ (2007) Mechanism of insulin-like growth factor I-mediated proliferation of adult neural progenitor cells: role of Akt. Eur J Neurosci 25:1041–1048

    Article  PubMed  Google Scholar 

  21. Jin Z, Liu L, Bian W, Chen Y, Xu G, Cheng L, Jing N (2009) Different transcription factors regulate nestin gene expression during P19 cell neural differentiation and central nervous system development. J Biol Chem 284:8160–8173

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Yuan H, Hu A, Zhang L, Zhu X (2012) Investigation of neural stem cell-specific regulatory promoter elements. Exp Ther Med 4:405–408

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Rafalski VA, Brunet A (2011) Energy metabolism in adult neural stem cell fate. Prog Neurobiol 93:182–203

    Article  CAS  PubMed  Google Scholar 

  24. Joseph D'Ercole A, Ye P (2008) Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958–5962

    Article  PubMed Central  PubMed  Google Scholar 

  25. Lunn JS, Pacut C, Backus C, Hong Y, Johe K, Hefferan M, Marsala M, Feldman EL (2010) The pleotrophic effects of insulin-like growth factor-I on human spinal cord neural progenitor cells. Stem Cells Dev 19:1–11

    Article  Google Scholar 

  26. Hodge RD, D’Ercole AJ, O’Kusky JR (2004) Insulin-like growth factor-I accelerates the cell cycle by decreasing G1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci 24:10201–10210

    Article  CAS  PubMed  Google Scholar 

  27. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11:309–317

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Ye P, Popken GJ, Kemper A, McCarthy K, Popko B, D’Ercole AJ (2004) Astrocyte specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression. J Neurosci Res 78:472–484

    Article  CAS  PubMed  Google Scholar 

  29. Yang X, Wei A, Liu Y, He G, Zhou Z, Yu Z (2013) IGF-1 protects retinal ganglion cells from hypoxia-induced apoptosis by activating the Erk-1/2 and Akt pathways. Mol Vis 19:1901–1912

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Yan YP, Sailor KA, Vemuganti R, Dempsey RJ (2006) Insulin-like growth factor-1 is an endogenous mediator of focal ischemia-induced neural progenitor proliferation. Eur J Neurosci 24:45–54

    Article  PubMed  Google Scholar 

  31. Samuels IS, Karlo JC, Faruzzi AN, Pickering K, Herrup K, Sweatt JD, Saitta SC, Landreth GE (2008) Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. J Neurosci 28:6983–6995

    Article  CAS  PubMed  Google Scholar 

  32. Chao J, Yang L, Buch S, Gao L (2013) Angiotensin II increased neuronal stem cell proliferation: role of AT2R. PLoS One 8:e63488

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Phoenix TN, Temple S (2010) Spred1, a negative regulator of Ras-MAPK-ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure. Genes Dev 24:45–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Hu X, Jin L, Feng L (2004) Erk1/2 but not PI3K pathway is required for neurotrophin 3-induced oligodendrocyte differentiation of post-natal neural stem cells. J Neurochem 90:1339–1347

    Article  CAS  PubMed  Google Scholar 

  35. Hu JG, Fu SL, Wang YX, Li Y, Jiang XY, Wang XF, Qiu MS, Lu PH, Xu XM (2008) Platelet-derived growth factor-AA mediates oligodendrocyte lineage differentiation through activation of extracellular signal-regulated kinase signaling pathway. Neuroscience 151:138–147

    Article  CAS  PubMed  Google Scholar 

  36. Ma DK, Ponnusamy K, Song MR, Ming GL, Song H (2009) Molecular genetic analysis of FGFR1 signalling reveals distinct roles of MAPK and PLCgamma1 activation for self-renewal of adult neural stem cells. Mol Brain 2:16

    Article  PubMed Central  PubMed  Google Scholar 

  37. Sato T, Shimazaki T, Naka H, Fukami S, Satoh Y, Okano H, Lax I, Schlessinger J, Gotoh N (2010) FRS2α regulates ERK levels to control a self-renewal target Hes1 and proliferation of FGF-responsive neural stem/progenitor cells. Stem Cells 28:1661–1673

    Article  PubMed Central  PubMed  Google Scholar 

  38. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating down stream. Cell 129:1261–1274

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mairet-Coello G, Tury A, DiCicco-Bloom E (2009) Insulin-like growth factor-1 promotes G(1)/S cell cycle progression through bidirectional regulation of cyclins and cyclin-dependent kinase inhibitors via the phosphatidylinositol 3-kinase/Akt pathway in developing rat cerebral cortex. J Neurosci 29:775–788

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Sinor AD, Lillien L (2004) Akt-1 expression level regulates CNS precursors. J Neurosci 24:8531–8541

    Article  CAS  PubMed  Google Scholar 

  41. Chung H, Li E, Kim Y, Kim S, Park S (2013) Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells. J Endocrinol 218:49–59

    Article  CAS  PubMed  Google Scholar 

  42. Peltier J, O’Neill A, Schaffer DV (2007) PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 67:1348–1361

    Article  CAS  PubMed  Google Scholar 

  43. Otaegi G, Yusta-Boyo MJ, Vergano-Vera E, Mendez-Gomez HR, Carrera AC, Abad JL, Gonzalez M, de la Rosa EJ, Vicario-Abejon C, de Pablo F (2006) Modulation of the PI3-kinase-Akt signaling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells. J Cell Sci 119:2739–2748

    Article  CAS  PubMed  Google Scholar 

  44. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  CAS  PubMed  Google Scholar 

  45. Mograbi B, Bocciardi R, Bourget I, Busca R, Rochet N, Farahi-Far D, Juhel T, Rossi B (2001) Glial cell line-derived neurotrophic factor-stimulated phosphatidylinositol 3-kinase and Akt activities exert opposing effects on the ERK pathway: importance for the rescue of neuroectodermic cells. J Biol Chem 276:45307–45319

    Article  CAS  PubMed  Google Scholar 

  46. Reusch HP, Zimmermann S, Schaefer M, Paul M, Moelling K (2001) Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J Biol Chem 276:33630–33637

    Article  CAS  PubMed  Google Scholar 

  47. Huang W, Zhao Y, Zhu X, Cai Z, Wang S, Yao S, Qi Z, Xie P (2013) Fluoxetine upregulates phosphorylated-AKT and phosphorylated-ERK1/2 proteins in neural stem cells: evidence for a crosstalk between AKT and ERK1/2 pathways. J Mol Neurosci 49:244–249

    Article  CAS  PubMed  Google Scholar 

  48. Cui QL, Almazan G (2007) IGF-I-induced oligodendrocyte progenitor proliferation requires PI3K/Akt, MEK/ERK, and Src-like tyrosine kinases. J Neurochem 100:1480–1493

    CAS  PubMed  Google Scholar 

  49. Chan WS, Sideris A, Sutachan JJ, Montoya GJV, Blanck TJ, Recio-Pinto E (2013) Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem/progenitors by ERK1/2, Akt, and PLCγ. Front Mol Neurosci 6:23

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The research was financially supported by the Natural Science Foundation of China (31172171), the Natural Science Foundation for youth in Jiangsu Province (BK2012138), the Natural Science Foundation of Jiangsu Province (BK2011209), and the President Foundation of Xuzhou Medical College (2012KJZ20). pNX7 vector was provided by Naihe Jing.

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Authors and Affiliations

  1. Research Center for Neurobiology, Xuzhou Medical College, Xuzhou, Jiangsu, China

    Honghua Yuan, Lianlian Wu, Tengye Zhang & Zhenzhen Wang

  2. Laboratory Animal Center, Xuzhou Medical College, Xuzhou, 221004, Jiangsu, China

    Renjin Chen, Quangang Chen, Ankang Hu & Xiaorong Zhu

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  1. Honghua Yuan
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  2. Renjin Chen
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  3. Lianlian Wu
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  4. Quangang Chen
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  7. Zhenzhen Wang
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  8. Xiaorong Zhu
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Correspondence to Xiaorong Zhu.

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Honghua Yuan, Renjin Chen and Lianlian Wu contributed equally to this work.

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Yuan, H., Chen, R., Wu, L. et al. The Regulatory Mechanism of Neurogenesis by IGF-1 in Adult Mice. Mol Neurobiol 51, 512–522 (2015). https://doi.org/10.1007/s12035-014-8717-6

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  • DOI: https://doi.org/10.1007/s12035-014-8717-6

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