Age-dependent decline in fate switch from NG2 cells to astrocytes after Olig2 deletion
- 1University of Connecticut, Department of Physiology and Neurobiology, 75 North Eagleville Road, Storrs, CT 06269-3156, USA
- 2Cincinnati Children's Hospital Medical Center, Department of Pediatrics, Cincinnati, OH
- 3University of Connecticut Institute of System Genomics and University of Connecticut Institute of Brain and Cognitive Sciences
- akiko.nishiyama{at}uconn.edu
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Author contributions: HZ, WMW, AS, and RAH performed experiments and contributed to figures, HZ, WMW, AS, and AN wrote the manuscript, QL contributed mouse line as well as design and discussion of the study.
Abstract
NG2 cells are a resident glial progenitor cell population that is uniformly distributed throughout the developing and mature mammalian central nervous system (CNS). Those in the postnatal CNS generate exclusively myelinating and non-myelinating oligodendrocytes and are hence equated with oligodendrocyte precursor cells (OPCs). Prenatally, NG2 cells in the ventral gray matter of the forebrain generate protoplasmic astrocytes as well as oligodendrocytes. The fate conversion from NG2 cells into protoplasmic astrocytes is dependent on downregulation of the key oligodendrocyte transcription factor Olig2. We previously showed that constitutive deletion of Olig2 in NG2 cells converts NG2 cells in the neocortex into protoplasmic astrocytes at the expense of oligodendrocytes. In this study, we show that postnatal deletion of Olig2 in both male and female mice caused NG2 cells in the neocortex but not in other gray matter regions to become protoplasmic astrocytes. However, NG2 cells in the neocortex became more resistant to astrocyte fate switch over the first three postnatal weeks. Fewer NG2 cells differentiated into astrocytes and did so with longer latency after Olig2 deletion at postnatal day 18 (P18) compared to deletion at P2. The high-mobility group transcription factor Sox10 was not downregulated for at least one month after Olig2 deletion at P18 despite an early transient upregulation of the astrocyte transcription factor NFIA. Furthermore, inhibiting cell proliferation in slice culture reduced astrocyte differentiation from Olig2-deleted perinatal NG2 cells, suggesting that cell division might facilitate nuclear reorganization needed for astrocyte transformation.
SIGNIFICANCE STATEMENT
NG2 cells are glial progenitor cells that retain a certain degree of lineage plasticity. In the normal postnatal neocortex, they generate mostly oligodendrocyte lineage cells. When the oligodendrocyte transcription factor Olig2 is deleted in NG2 cells in the neocortex, they switch their fate to protoplasmic astrocytes. However, the efficiency of the fate switch decreases with age over the first postnatal three weeks and is reduced when cell proliferation is inhibited. As the neocortex matures, sustained expression of oligodendrocyte lineage-specific key transcription factor Sox10 becomes less dependent on Olig2. Taken together, our findings suggest a gradual stabilization of the oligodendrocyte lineage genes and loss of lineage plasticity during the first three weeks after birth, possibly due to nuclear reorganization.
Footnotes
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The authors declare no competing financial interests.
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This study was funded by NIH R01NS049267, NIH R01 NS074870, and NIH R01 NS073425 to AN, NIH R01NS072427 and R01NS075243 (QRL), and Connecticut Stem Cell Program 06SCB03 (AN). The Leica SP8 confocal microscope was purchased using NIH Shared Instrumentation Grant S10OD016435 (PI, AN) and is maintained by Dr. Chris O'Connell, Director of Advanced Microscopy Facility. We thank Youfen Sun for maintaining the transgenic mouse colony. We thank Dr. Ben Deneen (Baylor College of Medicine) for the rabbit anti-NFIA antibody and Dr. Michael Wegner (Erlangen University) for the guinea pig anti-Sox10 antibody. The authors declare no competing financial interests.
- Received March 14, 2017.
- Revision received December 31, 2017.
- Accepted January 23, 2018.
- Copyright © 2018 the authors
