Paired Related Homeobox Protein 1 Regulates Quiescence in Human Oligodendrocyte Progenitors

Abstract

SUMMARY Human oligodendrocyte progenitor cells (hOPCs) persist into adulthood as an abundant precursor population capable of division and differentiation. The transcriptional mechanisms that regulate hOPC homeostasis remain poorly defined. Herein, we identify paired related homeobox protein 1 (PRRX1) in primary PDGFαR+ hOPCs. We show that enforced PRRX1 expression results in reversible G1/0 arrest. While both PRRX1 splice variants reduce hOPC proliferation, only PRRX1a abrogates migration. hOPC engraftment into hypomyelinated shiverer/rag2 mouse brain is severely impaired by PRRX1a, characterized by reduced cell proliferation and migration. PRRX1 induces a gene expression signature characteristic of stem cell quiescence. Both IFN-γ and BMP signaling upregulate PRRX1 and induce quiescence. PRRX1 knockdown modulates IFN-γ-induced quiescence. In mouse brain, PRRX1 mRNA was detected in non-dividing OPCs and is upregulated in OPCs following demyelination. Together, these data identify PRRX1 as a regulator of quiescence in hOPCs and as a potential regulator of pathological quiescence.

Oligodendrocyte Intrinsic miR-27a Controls Myelination and Remyelination

“…Despite upregulation of genes related to the cell cycle, miR-27a overexpression did not potentiate OPC proliferation. These results are consistent with previous findings (Wang et al, 2018), where the authors noted increased expression of cell-cycle inhibitors CDKN1A (p21 CIP ) and CDKN2B (p15 INK4B ) in PRRX1-induced hOPCs, as well as downregulation of CDKN1B (p57 KIP ) and CDKN2A (p16 INK4A ). Interestingly, we also found increased expression of CDK inhibitors (Cdkn1c and Cdkn2c) and genes (Emp1, Trp53inp1, Trp53i11, and Trp53i13) having anti-proliferative properties in miR-27a-overexpressing OPCs (Sun et al, 2014; Wu et al, 2009b), which might be responsible for the lower number of Edu+/Ki67+ cells in the presence of miR-27a in OPCs.…”

“…miR-27a is necessary for OPC lineage specification in rodent brains. Adult OPCs in both human and rodent brain remain in a state of quiescence with a prolonged cell cycle (Wang et al, 2018). The prolonged expression of miR-27a following the initial increase therefore supports the hypothesis that consistent expression of miR-27a is necessary to maintain cells in the quiescent state.…”

Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis

“…Promoting brain repair represents a potential strategy to restore neurological function in patients with PMS (10). However, the success of potential remyelinating therapies relies on endogenous oligodendrocyte progenitor cells (OPCs) to differentiate into myelinating oligodendrocytes (OLs) (11–15). Therefore, understanding what limits the potential of endogenous OPCs for remyelination will be required to realize remyelination as a therapeutic opportunity for regeneration.…”

Elucidating dynamics and regulation of alternative splicing in osteogenic differentiation

“…The OAR domain is involved in DNA binding and inhibition of transcription activation (Norris and Kern, 2001; Reichert et al, 2013). Previous studies have established that PRRX1a and PRRX1b act differentially to regulate progenitor cell proliferation and differentiation (Takano et al, 2016; Wang et al, 2018). Indeed, the sashimi plot in Figure S2C shows that the inclusion level of exon 4 decreased from 63% on day 0 to 41% on day 12, resulting in an isoform switch from the OAR-absent PRRX1B to the OAR-containing PRRX1A during induced MSPC osteogenesis.…”