Neuroscience Bulletin

, Volume 32, Issue 3, pp 205–216 | Cite as

Phosphofructokinase-1 Negatively Regulates Neurogenesis from Neural Stem Cells

  • Fengyun Zhang
  • Xiaodan Qian
  • Cheng Qin
  • Yuhui Lin
  • Haiyin Wu
  • Lei Chang
  • Chunxia Luo
  • Dongya ZhuEmail author
Original Article


Phosphofructokinase-1 (PFK-1), a major regulatory glycolytic enzyme, has been implicated in the functions of astrocytes and neurons. Here, we report that PFK-1 negatively regulates neurogenesis from neural stem cells (NSCs) by targeting pro-neural transcriptional factors. Using in vitro assays, we found that PFK-1 knockdown enhanced, and PFK-1 overexpression inhibited the neuronal differentiation of NSCs, which was consistent with the findings from NSCs subjected to 5 h of hypoxia. Meanwhile, the neurogenesis induced by PFK-1 knockdown was attributed to the increased proliferation of neural progenitors and the commitment of NSCs to the neuronal lineage. Similarly, in vivo knockdown of PFK-1 also increased neurogenesis in the dentate gyrus of the hippocampus. Finally, we demonstrated that the neurogenesis mediated by PFK-1 was likely achieved by targeting mammalian achaete-scute homologue-1 (Mash 1), neuronal differentiation factor (NeuroD), and sex-determining region Y (SRY)-related HMG box 2 (Sox2). All together, our results reveal PFK-1 as an important regulator of neurogenesis.


Phosphofructokinase-1 Neural stem cell Neurogenesis Neuronal differentiation Proliferation Hypoxia 



This work was supported by grants from the National Natural Science Foundation of China (91232304, 31530091, and 81571188), the National Basic Research Development Program (973 Program) of China (2011CB504404), the Natural Science Foundation of Jiangsu Province, China (BK2011029 and BK20130040), and the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine.


  1. 1.
    Temple S. The development of neural stem cells. Nature 2001, 414: 112–117.CrossRefPubMedGoogle Scholar
  2. 2.
    Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 2014, 94: 991–1026.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008, 132: 645–660.CrossRefPubMedGoogle Scholar
  4. 4.
    Kempermann G, Song H, Gage FH. Neurogenesis in the Adult Hippocampus. Cold Spring Harb Perspect Biol 2015, 7: a018812.CrossRefPubMedGoogle Scholar
  5. 5.
    Crowther AJ, Song J. Activity-dependent signaling mechanisms regulating adult hippocampal neural stem cells and their progeny. Neurosci Bull 2014, 30: 542–556.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005, 28: 223–250.CrossRefPubMedGoogle Scholar
  7. 7.
    Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 2006, 7: 179–193.CrossRefPubMedGoogle Scholar
  8. 8.
    Winner B, Winkler J. Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb Perspect Biol 2015, 7: a021287.CrossRefPubMedGoogle Scholar
  9. 9.
    Chern CM, Wang YH, Liou KT, Hou YC, Chen CC, Shen YC. 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke. Biochem Pharmacol 2014, 87: 502–514.CrossRefPubMedGoogle Scholar
  10. 10.
    Shen T, Pu J, Zheng T, Zhang B. Induced neural stem/precursor cells for fundamental studies and potential application in neurodegenerative diseases. Neurosci Bull 2015, 31: 589–600.CrossRefPubMedGoogle Scholar
  11. 11.
    Huang Y, Tan S. Direct lineage conversion of astrocytes to induced neural stem cells or neurons. Neurosci Bull 2015, 31: 357–367.CrossRefPubMedGoogle Scholar
  12. 12.
    Braunschweig L, Meyer AK, Wagenfuhr L, Storch A. Oxygen regulates proliferation of neural stem cells through Wnt/beta-catenin signalling. Mol Cell Neurosci 2015, 67: 84–92.CrossRefPubMedGoogle Scholar
  13. 13.
    Mor I, Cheung EC, Vousden KH. Control of glycolysis through regulation of PFK1: old friends and recent additions. Cold Spring Harb Symp Quant Biol 2011, 76: 211–216.CrossRefPubMedGoogle Scholar
  14. 14.
    Wehling-Henricks M, Oltmann M, Rinaldi C, Myung KH, Tidball JG. Loss of positive allosteric interactions between neuronal nitric oxide synthase and phosphofructokinase contributes to defects in glycolysis and increased fatigability in muscular dystrophy. Hum Mol Genet 2009, 18: 3439–3451.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sola-Penna M, Da Silva D, Coelho WS, Marinho-Carvalho MM, Zancan P. Regulation of mammalian muscle type 6-phosphofructo-1-kinase and its implication for the control of the metabolism. IUBMB Life 2010, 62: 791–796.CrossRefPubMedGoogle Scholar
  16. 16.
    Jenkins CM, Yang J, Sims HF, Gross RW. Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. J Biol Chem 2011, 286: 11937–11950.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Costa Leite T, Da Silva D, Guimaraes Coelho R, Zancan P, Sola-Penna M. Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis. Biochem J 2007, 408: 123–130.Google Scholar
  18. 18.
    Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J 2004, 381: 561–579.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA, 3rd, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012, 337: 975–980.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yalcin A, Telang S, Clem B, Chesney J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp Mol Pathol 2009, 86: 174–179.CrossRefPubMedGoogle Scholar
  21. 21.
    Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 2009, 11: 747–752.CrossRefPubMedGoogle Scholar
  22. 22.
    Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolanos JP. Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ 2012, 19: 1582–1589.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Almeida A, Almeida J, Bolanos JP, Moncada S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci U S A 2001, 98: 15294–15299.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Almeida A, Moncada S, Bolanos JP. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 2004, 6: 45–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Luo CX, Jin X, Cao CC, Zhu MM, Wang B, Chang L, et al. Bidirectional regulation of neurogenesis by neuronal nitric oxide synthase derived from neurons and neural stem cells. Stem Cells 2010, 28: 2041–2052.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhu LJ, Li TY, Luo CX, Jiang N, Chang L, Lin YH, et al. CAPON-nNOS coupling can serve as a target for developing new anxiolytics. Nat Med 2014, 20: 1050–1054.CrossRefPubMedGoogle Scholar
  27. 27.
    Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 2010, 65: 7–19.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hu M, Sun YJ, Zhou QG, Chen L, Hu Y, Luo CX, et al. Negative regulation of neurogenesis and spatial memory by NR2B-containing NMDA receptors. J Neurochem 2008, 106: 1900–1913.CrossRefPubMedGoogle Scholar
  29. 29.
    Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature 2002, 417: 39–44.CrossRefPubMedGoogle Scholar
  30. 30.
    Al Hasawi N, Alkandari MF, Luqmani YA. Phosphofructokinase: a mediator of glycolytic flux in cancer progression. Crit Rev Oncol Hematol 2014, 92: 312–321.Google Scholar
  31. 31.
    Luo CX, Lin YH, Qian XD, Tang Y, Zhou HH, Jin X, et al. Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. J Neurosci 2014, 34: 13535–13548.CrossRefPubMedGoogle Scholar
  32. 32.
    Ding Q, Liao SJ, Yu J. Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia. Neurosci Bull 2014, 30: 683–691.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang K, Zhao T, Huang X, Wu LY, Wu K, Zhu LL, et al. Notch1 mediates postnatal neurogenesis in hippocampus enhanced by intermittent hypoxia. Neurobiol Dis 2014, 64: 66–78.CrossRefPubMedGoogle Scholar
  34. 34.
    Zhao J, Gui M, Lu X, Jin D, Zhuang Z, Yan T. Electroacupuncture promotes neural stem cell proliferation and neurogenesis in the dentate gyrus of rats following stroke via upregulation of Notch1 expression. Mol Med Rep 2015, 12: 6911–6917.PubMedGoogle Scholar
  35. 35.
    Xiong W, Morillo SA, Rebay I. The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate in Drosophila photoreceptors. Development 2013, 140: 176–184.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wang X, Mao X, Xie L, Greenberg DA, Jin K. Involvement of Notch1 signaling in neurogenesis in the subventricular zone of normal and ischemic rat brain in vivo. J Cereb Blood Flow Metab 2009, 29: 1644–1654.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat Neurosci 2005, 8: 709–715.CrossRefPubMedGoogle Scholar
  38. 38.
    Raposo AA, Vasconcelos FF, Drechsel D, Marie C, Johnston C, Dolle D, et al. Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during Neurogenesis. Cell Rep. 2015, 10: 1544–1556.CrossRefGoogle Scholar
  39. 39.
    Gao Z, Ure K, Ables JL, Lagace DC, Nave KA, Goebbels S, et al. Neurod1 is essential for the survival and maturation of adult-born neurons. Nat Neurosci 2009, 12: 1090–1092.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Amador-Arjona A, Cimadamore F, Huang CT, Wright R, Lewis S, Gage FH, et al. SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proc Natl Acad Sci U S A 2015, 112: E1936–E1945.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Nakagomi T, Kubo S, Nakano-Doi A, Sakuma R, Lu S, Narita A, et al. Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. Stem Cells 2015, 33: 1962–1974.Google Scholar
  42. 42.
    Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A, et al. Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development 2004, 131: 3805–3819.CrossRefPubMedGoogle Scholar
  43. 43.
    Yang LC, Guo H, Zhou H, Suo DQ, Li WJ, Zhou Y, et al. Chronic oleoylethanolamide treatment improves spatial cognitive deficits through enhancing hippocampal neurogenesis after transient focal cerebral ischemia. Biochem Pharmacol 2015, 94: 270–281.CrossRefPubMedGoogle Scholar
  44. 44.
    Blaya MO, Tsoulfas P, Bramlett HM, Dietrich WD. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp Neurol 2015, 264: 67–81.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wang G, Xu Z, Wang C, Yao F, Li J, Chen C, et al. Differential phosphofructokinase-1 isoenzyme patterns associated with glycolytic efficiency in human breast cancer and paracancer tissues. Oncol Lett 2013, 6: 1701–1706.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 2015, 21: 392–402.CrossRefPubMedGoogle Scholar
  47. 47.
    Graham V, Khudyakov J, Ellis P, Pevny L. SOX2 functions to maintain neural progenitor identity. Neuron 2003, 39: 749–765.CrossRefPubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Science+Business Media Singapore 2016

Authors and Affiliations

  • Fengyun Zhang
    • 1
  • Xiaodan Qian
    • 1
  • Cheng Qin
    • 1
  • Yuhui Lin
    • 1
  • Haiyin Wu
    • 1
  • Lei Chang
    • 1
  • Chunxia Luo
    • 1
    • 2
    • 3
  • Dongya Zhu
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Pharmacology, School of PharmacyNanjing Medical UniversityNanjingChina
  2. 2.Institute of Stem Cells and NeuroregenerationNanjing Medical UniversityNanjingChina
  3. 3.Laboratory of Cerebrovascular DiseaseNanjing Medical UniversityNanjingChina
  4. 4.Key Laboratory of Human Functional Genomics of Jiangsu ProvinceNanjingChina

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