Nzf2 promotes oligodendrocyte differentiation and regeneration via repressing HDAC1-mediated histone deacetylation.

Proper axonal myelination and function of the vertebrate central nervous system rely largely on the timely differentiation of oligodendrocytes (OLs), yet key regulatory factors remain enigmatic. Our study reveals neural zinc finger (Nzf2) as a crucial orchestrator that controls the timing of OL differentiation both during development and myelin repair, contrasting with its previously suggested role in direct myelin gene regulation. ablation delays the onset of OL differentiation, while hyperactivation stimulates OL differentiation both during development and remyelination.

Hyperactivation of Hedgehog signaling impedes myelin development and repair via cholesterol dysregulation in oligodendrocytes.

The failure to remyelinate demyelinated axons poses a significant challenge in the treatment of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Here, we investigated the role of Hedgehog (Hh) signaling in myelin formation during development and under pathological conditions. Using conditional gain-of-function analyses, we found that hyperactivation of Hh signaling in oligodendrocyte precursor cells (OPCs) inhibits oligodendrocyte (OL) differentiation and myelination.

The committed oligodendrocyte precursor cell, a newly-defined intermediate progenitor cell type in oligodendroglial lineage.

In the central nervous system, oligodendrocytes (OLs) produce myelin sheaths that provide trophic support to neuronal axons and increase the propagation speed of action potential. OLs are constantly generated from OL precursor cells (OPCs) throughout life span. The production of myelinating OLs consists of three canonical stages: OPCs, newly-formed OLs (NFOs), and mature myelinating OLs.

Hedgehog Signaling in CNS Remyelination.

Remyelination is a fundamental repair process in the central nervous system (CNS) that is triggered by demyelinating events. In demyelinating diseases, oligodendrocytes (OLs) are targeted, leading to myelin loss, axonal damage, and severe functional impairment. While spontaneous remyelination often fails in the progression of demyelinating diseases, increased understanding of the mechanisms and identification of targets that regulate myelin regeneration becomes crucial.

Genetic Evidence that Dorsal Spinal Oligodendrocyte Progenitor Cells are Capable of Myelinating Ventral Axons Effectively in Mice.

In the developing spinal cord, the majority of oligodendrocyte progenitor cells (OPCs) are induced in the ventral neuroepithelium under the control of the Sonic Hedgehog (Shh) signaling pathway, whereas a small subset of OPCs are generated from the dorsal neuroepithelial cells independent of the Shh pathway. Although dorsally-derived OPCs (dOPCs) have been shown to participate in local axonal myelination in the dorsolateral regions during development, it is not known whether they are capable of migrating into the ventral region and myelinating ventral axons. In this study, we confirmed and extended the previous study on the developmental potential of dOPCs in the absence of ventrally-derived OPCs (vOPCs).

Stage-specific regulation of oligodendrocyte development by Hedgehog signaling in the spinal cord.

Elucidation of signaling pathways that control oligodendrocyte (OL) development is a prerequisite for developing novel strategies for myelin repair in neurological diseases. Despite the extensive work outlining the importance of Hedgehog (Hh) signaling in the commitment and generation of OL progenitor cells (OPCs), there are conflicting reports on the role of Hh signaling in regulating OL differentiation and maturation. In the present study, we systematically investigated OPC specification and differentiation in genetically modified mouse models of Smoothened (Smo), an essential component of the Hh signaling pathway in vertebrates.