Skip to main content

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

Virologica Sinica volume 32, pages 188–198 (2017)Cite this 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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Biran J, Tahor M, Wircer E, Levkowitz G. 2015. Role of developmental factors in hypothalamic function. Front Neuroanat, 9: 47.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Britt WJ, Mach M. 1996. Human cytomegalovirus glycoproteins. Intervirology, 39: 401–412.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Cinque P, Marenzi R, Ceresa D. 1997. Cytomegalovirus infections of the nervous system. Intervirology, 40: 85–97.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Episkopou V. 2005. SOX2 functions in adult neural stem cells. Trends Neurosci, 28: 219–221.

    CAS  PubMed  Google Scholar 

  • Fishell G, Kriegstein AR. 2003. Neurons from radial glia: the consequences of asymmetric inheritance. Curr Opin Neurobiol, 13: 34–41.

    CAS  PubMed  Google Scholar 

  • Fortini ME. 2009. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell, 16: 633–647.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Gaiano N, Fishell G. 2002. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci, 25: 471–490.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Gotz M, Huttner WB. 2005. The cell biology of neurogenesis. Nat Rev Mol Cell Biol, 6: 777–788.

    PubMed  Google Scholar 

  • Guerrini R, Parrini E. 2010. Neuronal migration disorders. Neurobiol Dis, 38: 154–166.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Hofman MA. 2014. Evolution of the human brain: when bigger is better. Front Neuroanat, 8: 15.

    PubMed  PubMed Central  Google Scholar 

  • Honjo T. 1996. The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells, 1: 1–9.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • Kageyama R, Ohtsuka T, Kobayashi T. 2008. Roles of Hes genes in neural development. Dev Growth Differ, 50 Suppl 1: S97–S103.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Lendahl U, Zimmerman LB, McKay RD. 1990. CNS stem cells express a new class of intermediate filament protein. Cell, 60: 585–595.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sejersen T, Lendahl U. 1993. Transient expression of the intermediate filament nestin during skeletal muscle development. J Cell Sci, 106(Pt 4): 1291–1300.

    CAS  PubMed  Google Scholar 

  • Selkoe D, Kopan R. 2003. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci, 26: 565–597.

    CAS  PubMed  Google Scholar 

  • Shimojo H, Ohtsuka T, Kageyama R. 2008. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron, 58: 52–64.

    CAS  PubMed  Google Scholar 

  • Sinzger C, Jahn G. 1996. Human cytomegalovirus cell tropism and pathogenesis. Intervirology, 39: 302–319.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (31600145).

Author information

Authors and Affiliations

  1. State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China

    Xi-Juan Liu, Xuan Jiang, Sheng-Nan Huang, Jin-Yan Sun, Fei Zhao, Wen-Bo Zeng & Min-Hua Luo

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Xi-Juan Liu

  3. The Joint Center of Translational Precision Medicine; Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, Guangzhou, 510000, China

    Xuan Jiang

Authors
  1. Xi-Juan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng-Nan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin-Yan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen-Bo Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Min-Hua Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wen-Bo Zeng or Min-Hua Luo.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, XJ., Jiang, X., Huang, SN. et al. Human cytomegalovirus infection dysregulates neural progenitor cell fate by disrupting Hes1 rhythm and down-regulating its expression. Virol. Sin. 32, 188–198 (2017). https://doi.org/10.1007/s12250-017-3956-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-017-3956-0

Keywords

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