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Ex Vivo Imaging of Postnatal Cerebellar Granule Cell Migration Using Confocal Macroscopy
Published on: May 12, 2015
Cytomegalovirus infection lengthens the cell cycle of granule cell precursors during postnatal cerebellar development
Cathy Yea Won Sung1,2, Mao Li3, Stipan Jonjic4,5
1Department of Microbiology, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama, USA.
Insights
Congenital human cytomegalovirus (HCMV) infection disrupts infant brain development. Murine CMV infection in newborn mice caused cerebellar hypoplasia by altering neural progenitor cell cycles, suggesting a mechanism for neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Virology
Background:
- Congenital human cytomegalovirus (HCMV) infection can cause neurodevelopmental disorders in infants.
- Mechanisms linking HCMV infection to altered neurodevelopment are not fully understood.
- A murine model of congenital cytomegalovirus (CMV) infection was previously established.
Purpose of the Study:
- To investigate the mechanisms by which murine CMV (MCMV) infection affects cerebellar development.
- To determine the impact of MCMV infection on cerebellar cortical development and neural progenitor cell cycle progression.
Main Methods:
- Congenital MCMV infection was established in newborn mice.
- Cerebellar development, including size and foliation, was assessed.
- Cell cycle progression of granule cell precursors (GCPs) was analyzed.
- The effect of TNF-α neutralization on MCMV-induced alterations was evaluated.
Main Results:
- MCMV infection led to reduced cerebellar size and foliation.
- Infected GCPs exhibited prolonged cell cycle duration and premature exit from the cell cycle.
- This resulted in a reduced number of granule cells (GCs) and cerebellar hypoplasia.
- Treatment with a TNF-α neutralizing antibody partially ameliorated GCP cell cycle alterations and cerebellar defects.
Conclusions:
- Virus-induced inflammation, specifically TNF-α, plays a role in altering GCP cell cycle progression during MCMV infection.
- Altered GCP cell cycle dynamics lead to reduced GC numbers and cerebellar hypoplasia.
- These findings provide a potential mechanism for neurodevelopmental abnormalities observed in HCMV-infected infants.
Abstract:
Human cytomegalovirus (HCMV) infection in infants infected in utero can lead to a variety of neurodevelopmental disorders. However, mechanisms underlying altered neurodevelopment in infected infants remain poorly understood. We have previously described a murine model of congenital HCMV infection in which murine CMV (MCMV) spreads hematogenously and establishes a focal infection in all regions of the brain of newborn mice, including the cerebellum. Infection resulted in disruption of cerebellar cortical development characterized by reduced cerebellar size and foliation. This disruption was associated with altered cell cycle progression of the granule cell precursors (GCPs), which are the progenitors that give rise to granule cells (GCs), the most abundant neurons in the cerebellum. In the current study, we have demonstrated that MCMV infection leads to prolonged GCP cell cycle, premature exit from the cell cycle, and reduced numbers of GCs resulting in cerebellar hypoplasia. Treatment with TNF-α neutralizing antibody partially normalized the cell cycle alterations of GCPs and altered cerebellar morphogenesis induced by MCMV infection. Collectively, our results argue that virus-induced inflammation altered the cell cycle of GCPs resulting in a reduced numbers of GCs and cerebellar cortical hypoplasia, thus providing a potential mechanism for altered neurodevelopment in fetuses infected with HCMV.
