Paired Related Homeobox Protein 1 Regulate Quiescence in Human Oligodendrocyte Progenitors
Sinha, Anjali K.
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Oligodendrocyte progenitor cells (OPCs) generate myelinating oligodendrocytes during CNS development, and persist into adulthood as an abundant population of glial precursors. The transcriptional mechanisms that regulate their homeostasis remain poorly defined. Our lab had previously identified paired related homeobox protein 1 (PRRX1), a known Sox2 co-factor, as a transcriptional regulator whose expression is up-regulated during specification of primary human (h)OPCs (Wang, Pol et al.). In previous work in our lab, we found that enforced PRRX1 expression in PDGFαR/CD140a + hOPCs resulted in G 0/1 arrest in vitro, leading to a profound inhibition of precursor expansion. While both PRRX1a and PRRX1b splice variants reduced proliferation of hOPCs, only PRRX1a abrogated progenitor migration in vitro. Furthermore, when PRRX1 overexpressing OPCs were transplanted into hypomyelinated shiverer mice, both cell migration and density of hOPCs were significantly decreased at 12 weeks post-implantation relative to control. Also, when PRRX1a and control hOPCs were transplanted into the same recipient, PRRX1a over-expression completely prevented engraftment. Therefore, the primary goal of this project is to understand the mechanism and regulation of PRRX1. In hOPCs, PRRX1 induced a gene expression signature characteristic of stem cell quiescence and directly induced expression of several cell-cycle inhibitors. We also found that both interferon-? and BMP signaling induced PRRX1 mRNA expression in hOPCs, indicating a common transcriptional response, and, more importantly, that PRRX1 is required for the induction of quiescence in hOPCs by both cytokines. Together, these data identify PRRX1 as a novel regulator of quiescence in hOPCs, and as a potential regulator of pathologically quiescent progenitor cells.