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. Through conditional gain‐of‐function strategy, we demonstrated that hyperactivation of Smo in neural progenitors induced transient ectopic OPC generation and precocious OL differentiation accompanied by the co‐induction of Olig2 and Nkx2.2. After the commitment of OL lineage, Smo activity is not required for OL differentiation, and sustained expression of Smo in OPCs stimulated cell proliferation but inhibited terminal differentiation. These findings have uncovered the stage‐specific regulation of OL development by Smo‐mediated Hh signaling, providing novel insights into the molecular regulation of OL differentiation and myelin repair.

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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. To date, several signaling pathways have been implicated in the remyelination process, including the Hedgehog (Hh) signaling pathway. This review summarizes the current data concerning the complicated roles of the Hh signaling pathway in the context of remyelination. We will highlight the open issues that have to be clarified prior to bringing molecules targeting the Hh signaling to demyelinating therapy.

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. Recently, single‐cell RNA transcriptomic analyses identified a new population of oligodendroglial cells, namely differentiation committed OPCs (COPs). COPs represent a critical intermediate population between OPCs and NFOs, as revealed by specific expression of G‐protein coupled receptor 17 (GPR17). The dysregulation of COPs leads to the remyelination failure in demyelinating diseases and impairs the replacement of lost myelin sheaths due to aging. Hence, understanding the development of COPs and their underlying regulatory network will be helpful in establishing new strategies for promoting myelin repair in demyelinating diseases. This review summarizes the current knowledge on the development and functions of COPs under both physiological and pathological conditions. Overall, COPs function as “checkpoints” to prevent inappropriate precocious OL differentiation and myelination through expressing distinct regulatory factors. Deepening our understanding of COPs may not only advance our knowledge of how OL lineage progresses during development, but also open the door to new treatments for demyelinating diseases.