DCX+ neuronal progenitors contribute to new oligodendrocytes during remyelination in the hippocampus

Abstract

A pool of different types of neural progenitor cells resides in the adult hippocampus. Apart from doublecortin-expressing (DCX+) neuronal progenitor cells (NPCs), the hippocampal parenchyma also contains oligodendrocyte precursor cells (OPCs), which can differentiate into myelinating oligodendrocytes. It is not clear yet to what extent the functions of these different progenitor cell types overlap and how plastic these cells are in response to pathological processes. The aim of this study was to investigate whether hippocampal DCX+ NPCs can generate new oligodendrocytes under conditions in which myelin repair is required. For this, the cell fate of DCX-expressing NPCs was analyzed during cuprizone-induced demyelination and subsequent remyelination in two regions of the hippocampal dentate gyrus of DCX-CreERT2/Flox-EGFP transgenic mice. In this DCX reporter model, the number of GFP+ NPCs co-expressing Olig2 and CC1, a combination of markers typically found in mature oligodendrocytes, was significantly increased in the hippocampal DG during remyelination. In contrast, the numbers of GFP+PDGFRα+ cells, as well as their proliferation, were unaffected by de- or remyelination. During remyelination, a higher portion of newly generated BrdU-labeled cells were GFP+ NPCs and there was an increase in new oligodendrocytes derived from these proliferating cells (GFP+Olig2+BrdU+). These results suggest that DCX-expressing NPCs were able to contribute to the generation of mature oligodendrocytes during remyelination in the adult hippocampus.

Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model

“…Although the effect of cuprizone treatment on hippocampal neurogenesis has not been extensively studied, our results agree with previous observations of reduced numbers of DCX+ cells in the cuprizone model (Abe et al, 2015). However, Klein et al found no significant differences in DCX+ cells after 1 or 2 wks remyelination but determined that DCX-expressing neural progenitors can contribute to the mature oligodendrocyte pool (Klein et al, 2020). The observation of increased OPC NG-2+ in hCX3CR1 I249/M280 mice point to an unexplored area regarding the use of FKN as an effective mediator for the interaction of new neurons and oligodendrocytes to enhance remyelination and repair.…”

Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via Ptpru and Dcx Modulation

“…Ptpru —a member of the R2B PTP family—regulates tyrosine phosphorylation and cadherin-based cell adhesion, and was found to be involved in CNS development [ 108 , 112 ]. Ptpru regulates neurite extension by inactivating β-catenin—a player in the Wnt signaling pathway [ 111 , 145 , 146 ]. The Wnt/β-catenin signaling pathway is a prominent regulator of differentiation of OPCs into mOLs [ 139 , 147 , 148 ].…”

“…This conjecture is consistent with the elevated anxiety levels we previously observed in NexKO mice compared to controls [ 56 ]. Moreover, it was recently shown that Dcx -enriched neuronal precursor cells are able to differentiate into mOLs in the murine hippocampus when demyelination is induced [ 146 ]. As was shown here and in previous studies, myelin and OL differentiation properties are aberrated in the brains of NexKO mice compared to controls [ 34 , 56 ].…”

“…As was shown here and in previous studies, myelin and OL differentiation properties are aberrated in the brains of NexKO mice compared to controls [ 34 , 56 ]. Hence, it is possible that this proposed myelination-repair mechanism [ 146 ] is faulted in the brains of NexKO mice, perhaps due to the alterations in miR-34b/c and Dcx expression levels, and their impact on neurogenesis. Furthermore, a recent study revealed that not only differentiating or migrating neurons, but also OPCs express Dcx , and that Dcx expression is downregulated in mOLs [ 154 ].…”

From sorting to sequencing in the molecular era: the evolution of the cancer stem cell model in medulloblastoma

“…Classic neurodevelopmental hierarchical model in which neural stem cells give rise to gradually more restricted progeny including neurons, oligodendrocytes and astrocytes. Emerging evidence has demonstrated additional complexity and plasticity within this hierarchical organization [114,115].…”