Glial Patchwork: Oligodendrocyte Progenitor Cells and Astrocytes Blanket the Central Nervous System

Tiling is a developmental process where cell populations become evenly distributed throughout a tissue. In this review, we discuss the developmental cellular tiling behaviors of the two major glial populations in the central nervous system (CNS)—oligodendrocyte progenitor cells (OPCs) and astrocytes. First, we discuss OPC tiling in the spinal cord, which is comprised of the three cellular behaviors of migration, proliferation, and contact-mediated repulsion (CMR). These cellular behaviors occur simultaneously during OPC development and converge to produce the emergent behavior of tiling which results in OPCs being evenly dispersed and occupying non-overlapping domains throughout the CNS. We next discuss astrocyte tiling in the cortex and hippocampus, where astrocytes migrate, proliferate, then ultimately determine their exclusive domains by gradual removal of overlap rather than sustained CMR. This results in domains that slightly overlap, allowing for both exclusive control of “synaptic islands” and astrocyte-astrocyte communication. We finally discuss the similarities and differences in the tiling behaviors of these glial populations and what remains unknown regarding glial tiling and how perturbations to this process may impact injury and disease.

mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system

In the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, which is essential for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR (Mechanistic Target of Rapamycin), which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both corpus callosum and spinal cord, Rictor loss in OPCs resulted in early reduction in myelin RNAs and some myelin proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin abundance and thickness was noted at post-natal day 21 and 1.5 months. By contrast, the losses in corpus callosum resulted in severe hypomyelination, and increased unmyelinated axons. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.

Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression

Olig2 is indispensable for motoneuron and oligodendrocyte fate-specification in the pMN domain of embryonic spinal cords, and also involved in the proliferation and differentiation of several cell types in the nervous system, including neural progenitor cells (NPCs) and oligodendrocytes. However, how Olig2 controls these diverse biological processes remains unclear. Here, we demonstrated that a novel Olig2-binding protein, DEAD-box helicase 20 (Ddx20), is indispensable for the survival of NPCs and oligodendrocyte progenitor cells (OPCs). A central nervous system (CNS)-specific Ddx20 conditional knockout (cKO) demonstrated apoptosis and cell cycle arrest in NPCs and OPCs, through the potentiation of the p53 pathway in DNA damage-dependent and independent manners, including SMN complex disruption and the abnormal splicing of Mdm2 mRNA. Analyzes of Olig2 null NPCs showed that Olig2 contributed to NPC proliferation through Ddx20 protein stabilization. Our findings provide novel mechanisms underlying the Olig2-mediated proliferation of NPCs, via the Ddx20-p53 axis, in the embryonic CNS.

Child abuse associates with increased recruitment of perineuronal nets in the ventromedial prefrontal cortex: a possible implication of oligodendrocyte progenitor cells

Child abuse (CA) is a strong predictor of psychopathologies and suicide, altering normal trajectories of brain development in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which orchestrate the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons into neuronal circuits. Using well-characterized post-mortem brain samples, we show that a history of CA is specifically associated with increased densities and morphological complexity of WFL-labeled PNNs in the ventromedial PFC (BA11/12), possibly suggesting increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in situ hybridization, we found that the expression of canonical components of PNNs is enriched in oligodendrocyte progenitor cells (OPCs), and that they are upregulated in CA victims. These correlational findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviors by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation.