Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation

Abstract

Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues.

Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence

“…Genes regulating OPC proliferation were both activated (Sox4 Article ll and Hes5) (Braccioli et al, 2018) and inhibited (Id2 and Gpr17) (Sock and Wegner, 2019). Likewise, genes promoting OPC differentiation were both activated (Kpna2) (Laitman et al, 2017) and inhibited (Olig1 and Olig2) (Sock and Wegner, 2019). These results suggest that both OPC recruitment and proliferation and OPC differentiation may be upregulated in distinct subsets of OPCs in response to the fast-refeed paradigm.…”

Importin α: functions as a nuclear transport factor and beyond

“…Indeed, by modulating the expression pattern of importin α subtypes in vitro , the expression changes of these importin α subtypes have demonstrated to be physiologically significant. For example, the expression patterns of importin α subtypes were shown to change during cell differentiation processes, and, more importantly, its modulation clearly affects cell differentiation processes such as the differentiation of embryonic stem cells into neural cells (KPNA1 73 ) ), myoblasts into myotubes (KPNA2 77 ) ), or maturation of oligodendrocyte progenitors (KPNA1, 80 ) KPNA4 78 ) ). However, it remains to be determined whether the changes in the nuclear transport of specific subsets of cargoes in fact alter differentiation processes.…”

Nutritional signals rapidly activate oligodendrocyte differentiation in the adult hypothalamic median eminence

“…Genes regulating OPC proliferation and maintenance in the cell cycle were both activated ( Sox4 , Hes5 ) 14 and inhibited ( Id2 , Gpr17 ) 15 . Likewise, genes promoting OPC differentiation and lineage progression were both activated ( Kpna2 , coordinator of transcriptional control of OL differentiation 16 ) and inhibited ( Olig1, Olig2) 15 . These results suggest that both OPC recruitment and proliferation and OPC differentiation may be upregulated in distinct subsets of OPCs in response to the fast-refeed paradigm.…”