Oligodendrogenesis in Evolution, Development and Adulthood

Abstract

Oligodendrogenesis and myelin formation are important processes in the central nervous system (CNS) of jawed vertebrates, underpinning the highly efficient neural computation within the compact CNS architecture. Myelin, the dense lipid sheath wrapped around axons, enables rapid signal transmission and modulation of neural circuits. Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), which are widely distributed in the adult CNS and continue to produce new oligodendrocytes throughout life. Adult oligodendrogenesis is integral to adaptive myelination, which fine-tunes neural circuits in response to neuronal activity, contributing to neuroplasticity, learning, and memory. Emerging evidence also highlights the role of oligodendrogenesis in specialized brain regions, linking oligodendrocytes to metabolic and homeostatic functions. In the aging and diseased brain, dysregulated oligodendrogenesis exacerbates myelin loss and may contribute to pathogenesis. In addition, maladaptive myelination driven by aberrant neuronal activity could sustain a dysfunction in conditions such as epilepsy. This review summarizes the current understanding of oligodendrogenesis, with insights into its evolution, regulation, and impact on aging and disease.

Keywords: adaptive myelination; development; evolution; maladaptive myelination; myelin; oligodendrocyte; oligodendrogenesis.

FIGURE 1

Oligodendrocyte lineage progression. OPCs originate from NSCs during neural development. These OPCs differentiate into pre‐myelinating oligodendrocytes, which subsequently mature into fully functional oligodendrocytes. Each stage is characterized by the expression of specific molecular markers.

FIGURE 2

Evolution of Oligodendrogenesis. In early vertebrate evolution, agnathans had not evolved myelin, with only Olig2 expressed in the CNS. In jawed fish, including chondrichthyans and osteichthyans, oligodendrocyte‐associated transcription factors such as Olig1 emerged, and Pdgfra‐negative OPCs of simple developmental origin could differentiate into oligodendrocytes marked by the expression of myelin proteins such as Mbp, Plp1, and P0. In amphibians, OPCs began to express Pdgfra; although P0 expression was restricted to the adult PNS, it was present in the CNS of tadpoles. Reptiles evolved gene expression profiles in oligodendrocyte lineage cells similar to those of mammals. Birds missed Olig1, which is critical to remyelination. Genes expressed in OPCs, oligodendrocytes, and oligodendrocyte lineage cells are written in green, red, and blue, respectively.

FIGURE 3

Models of OPC developmental origin in mouse cortex. (A) The first wave of OPCs arises from the medial ganglionic eminence (MGE), anterior entopeduncular area (AEP), and preoptic area (POA) in the ventral forebrain, followed by a second wave generated from the lateral ganglionic eminence (LGE), and a third wave originating postnatally within the developmental cortex. In this model, while MGE‐ and AEP/POA‐derived OPCs are eventually eliminated during development, LGE‐derived OPCs persist as the predominant source of OPCs and oligodendrocytes in the adult cortex (Kessaris et al. 2006). (B) Cortical OPCs and oligodendrocytes predominantly originate from MGE/AEP/POA as well as local cortical progenitors during development. This model reveals only minimal contribution from LGE to the adult cortical OPC/oligodendrocyte population (Li et al. 2024). (C) Progenitors within the developmental cortex are the primary source of cortical OPCs and oligodendrocytes in this model. While MGE and AEP/POA progenitors make a small but stable contribution to cortical OPCs, LGE‐derived cells primarily contribute to the piriform cortex (Cai et al. 2024).

FIGURE 4

Oligodendrogenesis in the adult brain. Neuronal electrical signals stimulate the differentiation of OPCs, resulting in oligodendrogenesis and localized myelin formation. Adaptive myelination, driven by experience‐induced neuronal activity, contributes to neuroplasticity, learning and memory. In contrast, maladaptive myelination, triggered by abnormal neuronal activity, may perpetuate dysfunctional neural circuits, underlying disorders such as epilepsy.