Skip to main content

Advertisement

Log in

Effects of rat cytomegalovirus on the nervous system of the early rat embryo

  • Research Article
  • Published:
Virologica Sinica

Abstract

The purpose of the study was to investigate the impact of rat cytomegalovirus (RCMV) infection on the development of the nervous system in rat embryos, and to evaluate the involvement of Wnt signaling pathway key molecules and the downstream gene neurogenin 1 (Ngn1) in RCMV infected neural stem cells (NSCs). Infection and control groups were established, each containing 20 pregnant Wistar rats. Rats in the infection group were inoculated with RCMV by intraperitoneal injection on the first day of pregnancy. Rat E20 embryos were taken to evaluate the teratogenic rate. NSCs were isolated from E13 embryos, and maintained in vitro. We found: 1) Poor fetal development was found in the infection group with low survival and high malformation rates. 2) The proliferation and differentiation of NSCs were affected. In the infection group, NSCs proliferated more slowly and had a lower neurosphere formation rate than the control. The differentiation ratio from NSCs to neurons and glial cells was significantly different from that of the control, showed by immunofluorescence staining. 3) Ngn1 mRNA expression and the nuclear β-catenin protein level were significantly lower than the control on day 2 when NSCs differentiated. 4) The Morris water maze test was performed on 4-week pups, and the infected rats were found worse in learning and memory ability. In a summary, RCMV infection caused abnormalities in the rat embryonic nervous system, significantly inhibited NSC proliferation and differentiation, and inhibited the expression of key molecules in the Wnt/β-catenin signaling pathway so as to affect NSCs differentiation. This may be an important mechanism by which RCMV causes embryonic nervous system abnormalities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Angulo A, Ghazal P, Messerle M. 2000. The major immediate-early gene ie3 of mouse cytomegalovirus is essential for viral growth. J Virol, 74: 11129–11136.

    Article  PubMed  CAS  Google Scholar 

  2. Arai Y, Ishiwata M, Baba S, et al. 2003. Neuron-specific activation of murine cytomegalovirus early gene e1 promoter in transgenic mice. Am J Pathol, 163:643–652.

    Article  PubMed  CAS  Google Scholar 

  3. Blader P, Lam C S, Rastegar S, et al. 2004. Conserved and acquired features of neurogenin1 regulation. Development, 131:5627–5637.

    Article  PubMed  CAS  Google Scholar 

  4. Cheeran M C, Lokensgard J R, Schleiss M R. 2009. Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev, 22:99–126.

    Article  PubMed  CAS  Google Scholar 

  5. Clevers H. 2009. Wnt/beta-catenin signaling in development and disease. Cell, 127:469–480.

    Article  Google Scholar 

  6. Ghazal P, Messerle M, Osborn K, et al. 2003. An essential role of the enhancer for murine cytomegalovirus in vivo growth and pathogenesis. J Virol, 77:3217–3228.

    Article  PubMed  CAS  Google Scholar 

  7. Gwak J, Hwang S G, Park H S, et al. 2012. Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation. Cell Res, 22:237–247.

    Article  PubMed  CAS  Google Scholar 

  8. Jan Y N, Jan L Y. 1993. HLH proteins, fly neurogenesis, and vertebrate myogenesis. Cell, 75:827–830.

    Article  PubMed  CAS  Google Scholar 

  9. Kléber M, Lee H Y, Wurdak H, et al. 2005. Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling. J Cell Biol, 169:309–320.

    Article  PubMed  Google Scholar 

  10. Li R Y, Baba S, Kosugi I, et al. 2001. Activation of murine cytomegalovirus immediate-early promoter in cerebral ventricular zone and glial progenitor cells in transgenic mice. Glia, 35:41–52.

    Article  PubMed  CAS  Google Scholar 

  11. Lie D C, Colamarino S A, Song H J, et al. 2005. Wnt signalling regulates adult hippocampal neurogenesis. Nature, 437:1370–1375.

    Article  PubMed  CAS  Google Scholar 

  12. Massari M E, Murre C. 2000. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol, 20:429–440.

    Article  PubMed  CAS  Google Scholar 

  13. Mazumdar J, O’Brien W T, Johnson R S, et al. 2010. O2 regulates stem cells through Wnt/β-catenin signalling. Nat Cell Biol, 12:1007–1013.

    Article  PubMed  CAS  Google Scholar 

  14. Morris R G M. 1981. Spatial localization does not require the presence of local cues. Learn Motiv, 12: 239–260.

    Article  Google Scholar 

  15. Murre C, McCaw P S, Vaessin H, et al. 1989. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell, 58:537–544.

    Article  PubMed  CAS  Google Scholar 

  16. Nieto M, Schuurmans C, Britz O, et al. 2001. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron, 29:401–413.

    Article  PubMed  CAS  Google Scholar 

  17. Schachtele S J, Mutnal M B, Schleiss M R, et al. 2011. Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol, 17:201–211.

    Article  PubMed  Google Scholar 

  18. Seto E S, Bellen H J. 2004. The ins and outs of Wingless signaling. Trends Cell Biol, 14:45–53.

    Article  PubMed  CAS  Google Scholar 

  19. Shinmura Y, Aiba-Masago S, Kosugi I, et al. 1997. Differential expression of the immediate-early and early antigens in neuronal and glial cells of developing mouse brains infected with murine cytomegalovirus. Am J Pathol, 151:1331–1340.

    PubMed  CAS  Google Scholar 

  20. Sun Y, Nadal-Vicens M, Misono S, et al. 2001. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell, 104:365–376.

    Article  PubMed  CAS  Google Scholar 

  21. Zechner D, Fujita Y, Hülsken J, et al. 2003. beta-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol, 258: 406–418.

    Article  PubMed  CAS  Google Scholar 

  22. Zheng H, Ying H, Wiedemeyer R, et al. 2010. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell, 17:497–509.

    Article  PubMed  CAS  Google Scholar 

  23. Zhou Y F, Fang F, Dong Y S, et al. 2006. Inhibitory effect of murine cytomegalovirus infection on neural stem cells differentiation and its mechanisms. Chin J Pediatr, 44:505–508. (in Chinese)

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhijun Liu.

Additional information

Foundation items: Shandong Province High-level Talent of Health 1020 Project Fund (No.2008-1); Science and Technology Creative Research of Weifang Medical University (No. K11TS1010); A Project of Shandong Province Higher Educational Science and Technology Program (No.J12LK04); National Natural Science Foundation of China (30900775).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, X., Guan, Y., Li, F. et al. Effects of rat cytomegalovirus on the nervous system of the early rat embryo. Virol. Sin. 27, 234–240 (2012). https://doi.org/10.1007/s12250-012-3250-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-012-3250-0

Keywords

Navigation