Abstract
Increased intracellular Ca2+ in oligodendrocyte progenitor cells (OPCs) is important to initiate their differentiation, but the intracellular Ca2+ channel involved in this process remains unclear. As a Ca2+-induced Ca2+ release (CICR) channel that mediates endoplasmic reticulum (ER) Ca2+ release, the role of ryanodine receptors (RyRs) in oligodendroglial development is unexplored. In the present study, we observed that among the three mammalian isoforms, oligodendroglial lineage cells selectively expressed RyR3. Strong RyR3-positive signal was distributed all over the cytoplasm and processes in OPCs and/or immature OLs (imOLs), whereas it gradually decreased and was located mainly around the perinuclear region in mature oligodendrocytes (OLs). In addition, RyR3-mediated intracellular Ca2+ waves following caffeine stimulation were correlated with the expression pattern of RyR3, in which high flat Ca2+ fluctuations and oscillatory Ca2+ waves were more frequently recorded in OPCs and/or imOLs than in OLs. Through further functional exploration, we demonstrated that pretreatment with the RyR antagonist ryanodine could neutralize the increase in intracellular Ca2+ induced by OPC differentiation and reduce the number of mature OLs. Moreover, gene-level knockdown of RyR3 by lentivirus in OPCs resulted in inhibition of OPC differentiation. Taken together, our results provide new insight into the crucial role of RyR3-mediated ER Ca2+ release in the regulation of OPC differentiation and/or myelination.
Highlights
In the CNS, myelinating oligodendrocytes (OLs) originate from oligodendrocyte progenitor cells (OPCs) after passing through a series of distinct developmental stages, i.e., OPCs, immature OLs and mature OLs (Stangel and Hartung, 2002)
The ryanodine receptor 3 (RyR3) mRNA level gradually decreased during OPC differentiation, and this downregulation tendency was further confirmed by western blot analysis (Figures 1C,D)
We found that RyR3 is the only ryanodine receptor (RyR) expressed in oligodendroglial cells and dynamically regulated during OPC differentiation
Summary
In the CNS, myelinating oligodendrocytes (OLs) originate from oligodendrocyte progenitor cells (OPCs) after passing through a series of distinct developmental stages, i.e., OPCs, immature OLs (imOLs) and mature OLs (Stangel and Hartung, 2002). RyR3 Function Regulates Oligodendroglial Differentiation demyelination diseases such as multiple sclerosis (MS; Wolswijk, 1998; Chang et al, 2002; Kuhlmann et al, 2008), promoting OPC differentiation into mature OLs becomes a promising approach for myelin repair. As a critical functional pattern of non-excitable glia cells, Ca2+ signaling is essential for oligodendroglial differentiation and myelination (Kirischuk et al, 1995; Cohen et al, 1996; Yoo et al, 1999; Soliven, 2001; Fulton et al, 2010; Cheli et al, 2015; Friess et al, 2016; Baraban et al, 2018; Krasnow et al, 2018). The Ca2+ channels involved in oligodendroglial differentiation is believed to be important but remains largely unexplored
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