Virologica Sinica

, Volume 32, Issue 3, pp 188–198

Human cytomegalovirus infection dysregulates neural progenitor cell fate by disrupting Hes1 rhythm and down-regulating its expression

Research Article

Abstract

Human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily affecting the central nervous system and causing its maldevelopment. As the essential downstream effector of Notch signaling pathway, Hes1, and its dynamic expression, plays an essential role on maintaining neural progenitor /stem cells (NPCs) cell fate and fetal brain development. In the present study, we reported the first observation of Hes1 oscillatory expression in human NPCs, with an approximately 1.5 hour periodicity and a Hes1 protein half-life of about 17 (17.6 ± 0.2) minutes. HCMV infection disrupts the Hes1 rhythm and down-regulates its expression. Furthermore, we discovered that depleting Hes1 protein disturbed NPCs cell fate by suppressing NPCs proliferation and neurosphere formation, and driving NPCs abnormal differentiation. These results suggested a novel mechanism linking disruption of Hes1 rhythm and down-regulation of Hes1 expression to neurodevelopmental disorders caused by congenital HCMV infection.

Keywords

human cytomegalovirus (HCMV) neural progenitor cells (NPCs) Hes1 rhythm cell fate 

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References

  1. Adland E, Klenerman P, Goulder P, Matthews PC. 2015. Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. Front Microbiol, 6: 1016.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ajiro M, Zheng ZM. 2015. E6.E7, a novel splice isoform protein of human papillomavirus 16, stabilizes viral E6 and E7 oncoproteins via HSP90 and GRP78. MBio, 6: e02068–02014.CrossRefGoogle Scholar
  3. Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD. 2001. A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci, 2: 287–293.CrossRefPubMedGoogle Scholar
  4. Biran J, Tahor M, Wircer E, Levkowitz G. 2015. Role of developmental factors in hypothalamic function. Front Neuroanat, 9: 47.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA. 1992. Symptomatic Congenital Cytomegalovirus-Infection- Neonatal Morbidity and Mortality. Pediatric Infectious Disease Journal, 11: 93–99.CrossRefPubMedGoogle Scholar
  6. Britt WJ, Mach M. 1996. Human cytomegalovirus glycoproteins. Intervirology, 39: 401–412.CrossRefPubMedGoogle Scholar
  7. Casavant NC, Luo MH, Rosenke K, Winegardner T, Zurawska A, Fortunato EA. 2006. Potential role for p53 in the permissive life cycle of human cytomegalovirus. J Virol, 80: 8390–8401.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cau E, Gradwohl G, Casarosa S, Kageyama R, Guillemot F. 2000. Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Development, 127: 2323–2332.PubMedGoogle Scholar
  9. Cinque P, Marenzi R, Ceresa D. 1997. Cytomegalovirus infections of the nervous system. Intervirology, 40: 85–97.CrossRefPubMedGoogle Scholar
  10. Conboy TJ, Pass RF, Stagno S, Britt WJ, Alford CA, McFarland CE, Boll TJ. 1986. Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics, 77: 801–806.PubMedGoogle Scholar
  11. Episkopou V. 2005. SOX2 functions in adult neural stem cells. Trends Neurosci, 28: 219–221.CrossRefPubMedGoogle Scholar
  12. Fishell G, Kriegstein AR. 2003. Neurons from radial glia: the consequences of asymmetric inheritance. Curr Opin Neurobiol, 13: 34–41.CrossRefPubMedGoogle Scholar
  13. Fortini ME. 2009. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell, 16: 633–647.CrossRefPubMedGoogle Scholar
  14. Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. 1997. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr, 130: 624–630.CrossRefPubMedGoogle Scholar
  15. Fu YR, Liu XJ, Li XJ, Shen ZZ, Yang B, Wu CC, Li JF, Miao LF, Ye HQ, Qiao GH, Rayner S, Chavanas S, Davrinche C, Britt WJ, Tang Q, McVoy M, Mocarski E, Luo MH. 2015. MicroRNA miR-21 attenuates human cytomegalovirus replication in neural cells by targeting Cdc25a. J Virol, 89: 1070–1082.CrossRefPubMedGoogle Scholar
  16. Gaiano N, Fishell G. 2002. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci, 25: 471–490.CrossRefPubMedGoogle Scholar
  17. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA. 1998. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell, 92: 63–72.CrossRefPubMedGoogle Scholar
  18. Goderis J, De Leenheer E, Smets K, van Hoecke H, Keymeulen A, Dhooge I. 2014. Hearing loss and congenital CMV infection: a systematic review. Pediatrics, 134: 972–982.CrossRefPubMedGoogle Scholar
  19. Gotz M, Huttner WB. 2005. The cell biology of neurogenesis. Nat Rev Mol Cell Biol, 6: 777–788.CrossRefPubMedGoogle Scholar
  20. Guerrini R, Parrini E. 2010. Neuronal migration disorders. Neurobiol Dis, 38: 154–166.CrossRefPubMedGoogle Scholar
  21. Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R. 2004. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development, 131: 5539–5550.CrossRefPubMedGoogle Scholar
  22. Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R. 2002. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science, 298: 840–843.CrossRefPubMedGoogle Scholar
  23. Hofman MA. 2014. Evolution of the human brain: when bigger is better. Front Neuroanat, 8: 15.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Honjo T. 1996. The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells, 1: 1–9.CrossRefPubMedGoogle Scholar
  25. Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F. 1995. Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes & Development, 9: 3136–3148.CrossRefGoogle Scholar
  26. Kageyama R, Ohtsuka T, Kobayashi T. 2008. Roles of Hes genes in neural development. Dev Growth Differ, 50 Suppl 1: S97–S103.CrossRefPubMedGoogle Scholar
  27. Kageyama R, Ohtsuka T, Shimojo H, Imayoshi I. 2009. Dynamic regulation of Notch signaling in neural progenitor cells. Curr Opin Cell Biol, 21: 733–740.CrossRefPubMedGoogle Scholar
  28. Koh K, Lee K, Ahn JH, Kim S. 2009. Human cytomegalovirus infection downregulates the expression of glial fibrillary acidic protein in human glioblastoma U373MG cells: identification of viral genes and protein domains involved. J Gen Virol, 90: 954–962.CrossRefPubMedGoogle Scholar
  29. Lendahl U, Zimmerman LB, McKay RD. 1990. CNS stem cells express a new class of intermediate filament protein. Cell, 60: 585–595.CrossRefPubMedGoogle Scholar
  30. Li XJ, Liu XJ, Yang B, Fu YR, Zhao F, Shen ZZ, Miao LF, Rayner S, Chavanas S, Zhu H, Britt WJ, Tang Q, McVoy MA, Luo MH. 2015. Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells. J Virol, 89: 6792–6804.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Luo MH, Hannemann H, Kulkarni AS, Schwartz PH, O’Dowd JM, Fortunato EA. 2010. Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells. J Virol, 84: 3528–3541.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Luo MH, Schwartz PH, Fortunato EA. 2008. Neonatal neural progenitor cells and their neuronal and glial cell derivatives are fully permissive for human cytomegalovirus infection. J Virol, 82: 9994–10007.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Masamizu Y, Ohtsuka T, Takashima Y, Nagahara H, Takenaka Y, Yoshikawa K, Okamura H, Kageyama R. 2006. Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc Natl Acad Sci U S A, 103: 1313–1318.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R. 1999. Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. Embo Journal, 18: 2196–2207.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R. 2001. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. Journal of Biological Chemistry, 276: 30467–30474.CrossRefPubMedGoogle Scholar
  36. Pan X, Li XJ, Liu XJ, Yuan H, Li JF, Duan YL, Ye HQ, Fu YR, Qiao GH, Wu CC, Yang B, Tian XH, Hu KH, Miao LF, Chen XL, Zheng J, Rayner S, Schwartz PH, Britt WJ, Xu J, Luo MH. 2013. Later passages of neural progenitor cells from neonatal brain are more permissive for human cytomegalovirus infection. J Virol, 87: 10968–10979.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Pass RF, Stagno S, Myers GJ, Alford CA. 1980. Outcome of symptomatic congenital cytomegalovirus infection: results of long-term longitudinal follow-up. Pediatrics, 66: 758–762.PubMedGoogle Scholar
  38. Qiao GH, Zhao F, Cheng S, Luo MH. 2016. Multipotent mesenchymal stromal cells are fully permissive for human cytomegalovirus infection. Virol Sin, 31: 219–228.CrossRefPubMedGoogle Scholar
  39. Sejersen T, Lendahl U. 1993. Transient expression of the intermediate filament nestin during skeletal muscle development. J Cell Sci, 106(Pt 4): 1291–1300.PubMedGoogle Scholar
  40. Selkoe D, Kopan R. 2003. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci, 26: 565–597.CrossRefPubMedGoogle Scholar
  41. Shimojo H, Ohtsuka T, Kageyama R. 2008. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron, 58: 52–64.CrossRefPubMedGoogle Scholar
  42. Sinzger C, Jahn G. 1996. Human cytomegalovirus cell tropism and pathogenesis. Intervirology, 39: 302–319.CrossRefPubMedGoogle Scholar
  43. Sossey-Alaoui K, Hartung AJ, Guerrini R, Manchester DK, Posar A, Puche-Mira A, Andermann E, Dobyns WB, Srivastava AK. 1998. Human doublecortin (DCX) and the homologous gene in mouse encode a putative Ca2+-dependent signaling protein which is mutated in human X-linked neuronal migration defects. Hum Mol Genet, 7: 1327–1332.CrossRefPubMedGoogle Scholar
  44. Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH. 2007. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell, 1: 515–528.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Takebayashi K, Sasai Y, Sakai Y, Watanabe T, Nakanishi S, Kageyama R. 1994. Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem, 269: 5150–5156.PubMedGoogle Scholar
  46. Tomita K, Ishibashi M, Nakahara K, Ang SL, Nakanishi S, Guillemot F, Kageyama R. 1996. Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron, 16: 723–734.CrossRefPubMedGoogle Scholar
  47. Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T. 2003. Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord, 33: 455–459.CrossRefPubMedGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Science+Business Media Singapore 2017

Authors and Affiliations

  1. 1.State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Wuhan Institute of VirologyChinese Academy of SciencesWuhanChina
  2. 2.University of Chinese Academy of SciencesBeijingChina
  3. 3.The Joint Center of Translational Precision Medicine; Guangzhou Institute of PediatricsGuangzhou Women and Children Medical CenterGuangzhouChina

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