Oligodendrocyte-lineage cell exocytosis and L-type prostaglandin D synthase promote oligodendrocyte development and myelination

Abstract

In the developing central nervous system, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes, which form myelin around axons. Oligodendrocytes and myelin are essential for the function of the central nervous system, as evidenced by the severe neurological symptoms that arise in demyelinating diseases such as multiple sclerosis and leukodystrophy. Although many cell-intrinsic mechanisms that regulate oligodendrocyte development and myelination have been reported, it remains unclear whether interactions among oligodendrocyte-lineage cells (OPCs and oligodendrocytes) affect oligodendrocyte development and myelination. Here, we show that blocking vesicle-associated membrane protein (VAMP) 1/2/3-dependent exocytosis from oligodendrocyte-lineage cells impairs oligodendrocyte development, myelination, and motor behavior in mice. Adding oligodendrocyte-lineage cell-secreted molecules to secretion-deficient OPC cultures partially restores the morphological maturation of oligodendrocytes. Moreover, we identified L-type prostaglandin D synthase as an oligodendrocyte-lineage cell-secreted protein that promotes oligodendrocyte development and myelination in vivo. These findings reveal a novel autocrine/paracrine loop model for the regulation of oligodendrocyte and myelin development.

CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes

“…2d). In support of this interpretation, iBot expression in oligodendrocyte-lineage cells using two different Cre lines (NG2-Cre and PDGFRa-CreERT2) caused similar myelin defects as iBot;Cnp-Cre, including decreased white matter area and hypomyelination 85,86 . Although we cannot exclude that iBot expression outside of oligodendrocyte-lineage cells contributed to reduced mouse body weight and premature death, mice mutants that are unable to assemble nodes of Ranvier in the CNS exhibited premature death within 2-3 weeks of birth, consistent with the phenotype and consequence of our iBot;Cnp-Cre mice 52 .…”

“…Potential explanations include the possibility that the cell-intrinsic upregulation of VAMP2/3 during differentiation outcompetes iBot activity, leading to incomplete cleavage of VAMP2/3 at later stages, or that VAMP2/3-independent mechanisms of membrane addition (such as the iBot-insensitive VAMP7 discussed above) may compensate at later stages. Although our study has uncovered critical roles for VAMP2/3 in membrane addition and adhesion protein localization, VAMP2/3-mediated exocytosis may also regulate myelination through the proper localization of cell-surface receptors necessary for growth factor signaling and/or the secretion of soluble signals 86 . How oligodendrocyte exocytosis mediates intercellular communication among glia and neurons, and how those mechanisms may be coupled to myelin membrane expansion, remains a ripe area for future investigation.…”

Presentation and integration of multiple signals that modulate oligodendrocyte lineage progression and myelination

“…OL lineage cells employ SNARE-mediated membrane fusion to enable secretion, vesicle, and membrane trafficking, as well as targeting and sorting of membrane proteins, which provide crucial functions at each of the different stages in OL development (Feldmann et al, 2011 ). Recently, we and others have shown that genetic expression of Vamp1, 2, and 3-specific B type botulinum toxin (BoNT/B), in OPCs using Cspg4-cre (Fekete et al, 2022 ) or Pdgfra-creERT (Pan et al, 2022 ) or in newly differentiated OLs using Cnp-cre (Lam et al, 2022 ) leads to severe hypomyelination due to inability of the Vamp2/3-cleaved OLs to produce myelin membranes. These findings suggest that a critical autocrine factor that is either secreted from newly generated OLs or is inserted into the plasma membrane of new OLs plays a critical role in myelination.…”