Abstract
Since the discovery of its role as a morphogen directing ventral patterning of the spinal cord, the secreted protein Sonic Hedgehog (Shh) has been implicated in a wide array of events contributing to the development, maintenance and repair of the central nervous system (CNS). One of these events is the generation of oligodendrocytes, the glial cells of the CNS responsible for axon myelination. In embryo, the first oligodendroglial cells arise from the ventral ventricular zone in the developing brain and spinal cord where Shh induces the basic helix-loop-helix transcription factors Olig1 and Olig2 both necessary and sufficient for oligodendrocyte production. Later on, Shh signaling participates in the production of oligodendroglial cells in the dorsal ventricular-subventricular zone in the postnatal forebrain. Finally, the modulation of Hedgehog signaling activity promotes the repair of demyelinated lesions. This mini-review article focuses on the Shh-dependent molecular mechanisms involved in the spatial and temporal control of oligodendrocyte lineage appearance. The apparent intricacy of the roles of two essential components of Shh signaling, Smoothened and Gli1, in the postnatal production of myelin and its regeneration following a demyelinating event is also highlighted. A deeper understanding of the implication of each of the components that regulate oligodendrogenesis and myelination should beneficially influence the therapeutic strategies in the field of myelin diseases.
Highlights
The generation of oligodendrocyte progenitor cells (OPCs) comprises several spatiotemporal waves localized firstly in ventral regions of the central nervous system (CNS) and slightly later in more dorsal domains
This species difference is related to the involvement of additional Hedgehog homologs (Table 1) including Indian Hedgehog b (Ihhb) and Tiggy winckle (Twhh) expressed in the notochord and/or floorplate during motoneuron and OPC specification (Krauss et al, 1993; Ekker et al, 1995; Park et al, 2002; Chung et al, 2013)
This accumulation was attributed to the activity of sulfatase1, which appears a short time before OPC specification in mouse and chicken embryos where the enzyme regulates the sulfation of heparin sulfate proteoglycans (HSPGs) (Figure 1B)
Summary
Small Molecules of Neuroprotection, Neuroregeneration and Remyelination – U1195, INSERM, University Paris-Sud/Paris-Saclay, Kremlin-Bicêtre, France. Since the discovery of its role as a morphogen directing ventral patterning of the spinal cord, the secreted protein Sonic Hedgehog (Shh) has been implicated in a wide array of events contributing to the development, maintenance and repair of the central nervous system (CNS). One of these events is the generation of oligodendrocytes, the glial cells of the CNS responsible for axon myelination. The modulation of Hedgehog signaling activity promotes the repair of demyelinated lesions This mini-review article focuses on the Shh-dependent molecular mechanisms involved in the spatial and temporal control of oligodendrocyte lineage appearance. A deeper understanding of the implication of each of the components that regulate oligodendrogenesis and myelination should beneficially influence the therapeutic strategies in the field of myelin diseases
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