Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development

Abstract

SummaryPdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different oligodendrocyte (OL) states at adult stages. Here, we present bulk and single-cell transcriptomics resources providing insights on how transitions between these states occur. We found that post-natal OPCs from brain and spinal cord present similar transcriptional signatures. Moreover, post-natal OPC progeny of E13.5 Pdgfra+ cells present electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves, indicating that Pdgfra+ pre-OPCs rewire their transcriptional network during development. Single-cell RNA-seq and lineage tracing indicates that a subset of E13.5 Pdgfra+ cells originates cells of the pericyte lineage. Thus, our results indicate that embryonic Pdgfra+ cells in the CNS give rise to distinct post-natal cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions.

Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes

“…Compared to two recently reported imOL markers Enpp6 (Xiao et al, ) and Bcas1 (Fard et al, ), Pcdh17it expression seems to better align with an intermediate stage between OPs and mature OLs, hence providing higher specificity for imOLs (Figures , and ; Figures S1 and S5a–d). Enpp6 is also weakly expressed in mature OLs with high levels of co‐localization (~90%) with CC1, and Bcas1 was also detected in some mature OLs, agreeing with data from a recently published single cell RNA‐seq database for OL lineage cells (Marques et al, ; Marques et al, ; Figure S5c–d). This database categorizes gene expression into 13 different OL subtype/developmental stage clusters (Figure S5a) and reveals that Pcdh17it expression is elevated in two clusters of newly formed imOLs while Enpp6 and Bcas1 expression is scattered in numerous clusters of OL subtypes/stages (Figure S5b–d).…”

“…Therefore, to streamline research into OL developmental dynamics in vivo, it is important to discover new gene products that can distinguish premyelinating imOLs from both myelinating OLs and OPs in tissue sections. In recent years, high‐throughput technologies such as transcriptome profiling, single‐cell sequencing, and proteomics have helped build informative databases covering OL lineage cells (Cahoy et al, ; Marques et al, ; Marques et al, ; Sharma et al, ; Zhang et al, ). Here, tapping into available data, we identify an OL lineage‐specific long noncoding RNA (lncRNA; Zhang et al, ) that is down‐regulated in myelinating OLs and provide evidence that this lncRNA (named Pcdh17it ) is a specific marker for immature, premyelinating imOLs.…”

Diversity in the oligodendrocyte lineage: Plasticity or heterogeneity?

“…The ablation of any one of the three distinct OPC populations did not, however, cause a reduction in the total number of OLCs at P12 or in myelination in adult mice (Kessaris et al, ), indicating that different OLCs can functionally compensate for one another. RNA‐sequencing data support these findings, as no differences in the gene expression profile between the developmentally distinct OPC populations has been detected (Marques et al, ). Whether ventrally and dorsally derived oligodendrocytes show transcriptional differences remains to be investigated.…”

“…Whether the transcriptionally different oligodendrocyte populations fulfil distinct functions in the brain remains to be investigated. These findings raise several important questions including, how can transcriptional diversity of oligodendrocytes arise from transcriptionally homogenous OPCs (Marques et al, )? Possible explanations include technical limitations of the sequencing technique to study gene expression in OPCs (limited amounts of RNA, fragility of OPC population) or environmental influences exerted during, or after, the oligodendrocyte differentiation process.…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…Thus, more than 500 molecularly distinct classes of neurons and glial cells have been identified in the mouse brain [1,2], and information about the cellular composition of specific brain regions is increasing rapidly [2][3][4][5][6][7][8]. In addition, there is an even larger number of supporting glial cells, i.e., astrocytes and oligodendrocytes, the latter forming myelin sheets around neurons and making up a large part of the white matter in the brain.…”