Title

Fate analysis of NG2 cells in vitro and in vivo

Date of Completion

January 2009

Keywords

Biology, Neurobiology

Degree

Ph.D.

Abstract

NG2 cells are a novel and unique cell population in the central nervous system. They were identified as the fourth type of glial cells, but their role as progenitor cells has not been well defined. Using newly generated transgenic mouse lines, we analyzed the fate of NG2 cells in vitro and in vivo, and demonstrated that NG2 cells are committed to glial lineage throughout development. ^ We purified NG2 cells from neonatal NG2DsRed BAC transgenic mice and found that NG2 cells give rise to oligodendrocytes, astrocytes but not neurons in vitro. Using NG2creBAC:ZEG double transgenic mice, we demonstrated for the first time that NG2 cells generate oligodendrocytes throughout the brain and a subset of protoplasmic astrocytes in ventral gray matter but not in dorsal neocortex or corpus callosum. NG2 cells generate some gray matter astrocytes in spinal cord but not in cerebellum. Neurons are not derived from NG2 cells, but some cortical neurons in the adult brain express the reporter due to the transient expression of Cre in these neurons. ^ Analysis on NG2creERTMBAC:ZEG double transgenic mice revealed that postnatal NG2 cells continuously generate oligodendrocytes even in the mature brain, and that the ability of NG2 cells to differentiate into oligodendrocytes declines with age. NG2 cells in the embryonic brain but not in the postnatal brain are capable of generating protoplasmic astrocytes in the ventral forebrain. Clusters of cells that arise from single NG2 cells in the postnatal brain are heterogeneous, containing pure oligodendrocytes, pure NG2 cells or both. ^ When the transcription factor Olig2 was deleted specifically in NG2 cells, NG2 cells predominantly generated astrocytes especially in the dorsal neocortex and corpus callosum at the expense of oligodendrocytes, indicating that the fate of NG2 cells toward oligodendrocytes or astrocytes can be switched by Olig2. ^ In summary, we clarified the fate of NG2 cells which had been under long debate and discovered an important regulatory mechanism underlying the differentiation of NG2 cells. Our work establishes the framework for understanding the progenitor property of NG2 cells so that the therapeutic function of NG2 cells can be better evaluated and applied to neurological diseases. ^