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Expressions of Forkhead Class Box O 3a on Crushed Rat Sciatic Nerves and Differentiated Primary Schwann cells

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Abstract

Forkhead box-containing protein, class O 3 a (FOXO3a), an Akt downstream target, plays an important role in peripheral nervous system. FOXO3a shares the ability to be inhibited and translocated from the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway. To elucidate the expression and possible function of FOXO3a in lesion and repair, we performed an acute sciatic nerve crush model and studied differential expressions of FOXO3a. We observed that expressions of FOXO3a in Schwann cells (SCs) of the peripheral nervous system and cAMP-induced differentiation were dynamically regulated. Western blot analysis showed FOXO3a level significantly decreased post injury. Moreover, Immunofluorescence double labeling suggested the changes were striking especially in SCs. In vitro, Western blot analysis showed that the expression of FOXO3a was decreased in cAMP-induced differentiated primary SCs. The FOXO3a siRNA-transfected SCs treated by cAMP promote differentiation of SCs through the PI3K/Akt pathway. The results indicate that FOXO3a plays an important role during differentiation of SCs.

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Abbreviations

SCs:

Schwann cells

FOXO3a:

Forkhead class box O 3a

PI3-K:

Phosphatidylinositol 3-kinase

P0:

Myelin protein zero

cAMP:

Cyclic adenosine monophosphate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

References

  • Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117:421–426

    Article  PubMed  CAS  Google Scholar 

  • Bakker WJ, Blazquez-Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Lowenberg B, von Lindern M, van Dijk TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1. J Cell Biol 164:175–184

    Article  PubMed  CAS  Google Scholar 

  • Birkenkamp KU, Essafi A, van der Vos KE, da Costa M, Hui RC, Holstege F, Koenderman L, Lam EW, Coffer PJ (2007) FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1. J Biol Chem 282:2211–2220

    Article  PubMed  CAS  Google Scholar 

  • Bois PR, Grosveld GC (2003) FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. EMBO J 22:1147–1157

    Article  PubMed  CAS  Google Scholar 

  • Brockes JP, Fields KL, Raff MC (1979) Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res 165:105–118

    Article  PubMed  CAS  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868

    Article  PubMed  CAS  Google Scholar 

  • Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME (2001) Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21:952–965

    Article  PubMed  CAS  Google Scholar 

  • Carlsson P, Mahlapuu M (2002) Forkhead transcription factors: key players in development and metabolism. Dev Biol 250:1–23

    Article  PubMed  CAS  Google Scholar 

  • Chandramohan V, Jeay S, Pianetti S, Sonenshein GE (2004) Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J Immunol 172:5522–5527

    PubMed  CAS  Google Scholar 

  • Fawcett JW, Keynes RJ (1990) Peripheral nerve regeneration. Annu Rev Neurosci 13:43–60

    Article  PubMed  CAS  Google Scholar 

  • Fu SY, Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol 14:67–116

    Article  PubMed  CAS  Google Scholar 

  • Heinen A, Kremer D, Gottle P, Kruse F, Hasse B, Lehmann H, Hartung HP, Kury P (2008) The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination. Proc Natl Acad Sci USA 105:8748–8753

    Article  PubMed  CAS  Google Scholar 

  • Hokfelt T, Zhang X, Wiesenfeld-Hallin Z (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 17:22–30

    Article  PubMed  CAS  Google Scholar 

  • Jessen KR, Mirsky R (2002) Signals that determine Schwann cell identity. J Anat 200:367–376

    Article  PubMed  CAS  Google Scholar 

  • Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464

    Article  PubMed  CAS  Google Scholar 

  • Kops GJ, Burgering BM (1999) Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med 77:656–665

    Article  PubMed  CAS  Google Scholar 

  • Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS (2003) Fox’s in development and disease. Trends Genet 19:339–344

    Article  PubMed  CAS  Google Scholar 

  • Lemke G, Chao M (1988) Axons regulate Schwann cell expression of the major myelin and NGF receptor genes. Development 102:499–504

    PubMed  CAS  Google Scholar 

  • Lenferink AE, Busse D, Flanagan WM, Yakes FM, Arteaga CL (2001) ErbB2/neu kinase modulates cellular p27(Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res 61:6583–6591

    PubMed  CAS  Google Scholar 

  • Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278:1319–1322

    Article  PubMed  CAS  Google Scholar 

  • Mathon NF, Malcolm DS, Harrisingh MC, Cheng L, Lloyd AC (2001) Lack of replicative senescence in normal rodent glia. Science 291:872–875

    Article  PubMed  CAS  Google Scholar 

  • Maurel P, Salzer JL (2000) Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J Neurosci 20:4635–4645

    PubMed  CAS  Google Scholar 

  • Miyazaki M, Babazono A, Ishii T, Sugie T, Momose Y, Iwahashi M, Une H (2002) Effects of low body mass index and smoking on all-cause mortality among middle-aged and elderly Japanese. J Epidemiol 12:40–44

    PubMed  Google Scholar 

  • Monje PV, Bartlett Bunge M, Wood PM (2006) Cyclic AMP synergistically enhances neuregulin-dependent ERK and Akt activation and cell cycle progression in Schwann cells. Glia 53:649–659

    Article  PubMed  Google Scholar 

  • Morgan L, Jessen KR, Mirsky R (1991) The effects of cAMP on differentiation of cultured Schwann cells: progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP-, N-CAM-, NGF-receptor-) depends on growth inhibition. J Cell Biol 112:457–467

    Article  PubMed  CAS  Google Scholar 

  • Nakae J, Kitamura T, Kitamura Y, Biggs WH III, Arden KC, Accili D (2003) The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell 4:119–129

    Article  PubMed  CAS  Google Scholar 

  • Nakao T, Geddis AE, Fox NE, Kaushansky K (2008) PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1). Cell Cycle 7:257–266

    Article  PubMed  CAS  Google Scholar 

  • Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999

    Article  PubMed  CAS  Google Scholar 

  • Sobue G, Shuman S, Pleasure D (1986) Schwann cell responses to cyclic AMP: proliferation, change in shape, and appearance of surface galactocerebroside. Brain Res 362:23–32

    Article  PubMed  CAS  Google Scholar 

  • Tran H, Brunet A, Griffith EC, Greenberg ME (2003) The many forks in FOXO’s road. Sci STKE 2003:RE5

  • Wang Y, Liu Y, Chen Y, Shi S, Qin J, Xiao F, Zhou D, Lu M, Lu Q, Shen A (2009) Peripheral nerve injury induces down-regulation of Foxo3a and p27kip1 in rat dorsal root ganglia. Neurochem Res 34:891–898

    Article  PubMed  CAS  Google Scholar 

  • Yamada H, Komiyama A, Suzuki K (1995) Schwann cell responses to forskolin and cyclic AMP analogues: comparative study of mouse and rat Schwann cells. Brain Res 681:97–104

    Article  PubMed  CAS  Google Scholar 

  • Yoon C, Korade Z, Carter BD (2008) Protein kinase A-induced phosphorylation of the p65 subunit of nuclear factor-kappaB promotes Schwann cell differentiation into a myelinating phenotype. J Neurosci 28:3738–3746

    Article  PubMed  CAS  Google Scholar 

  • Zheng WH, Kar S, Quirion R (2000) Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem 275:39152–39158

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr. Yuxiang Hu for helpful criticism and linguistic revision of the manuscript. This work was supported by the National Natural Science Foundation of China (No. 30770488, No. 30870320, No. 31070723, and No. 81070275); Natural Science Foundation of Jiangsu province (No. BK2009156, No. BK2009157, and No. BK2010169).

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Correspondence to Yuhong Ji or Huiguang Yang.

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First two authors contributed equally to this study.

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Wang, Q., Wang, Y., Zhou, Z. et al. Expressions of Forkhead Class Box O 3a on Crushed Rat Sciatic Nerves and Differentiated Primary Schwann cells. Cell Mol Neurobiol 31, 509–518 (2011). https://doi.org/10.1007/s10571-010-9644-3

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