Abstract
The Hedgehog morphogen aroused an enormous interest since it was characterized as an essential signal for ventral patterning of the spinal cord two decades ago. The pathway is notably implicated in the initial appearance of the progenitors of oligodendrocytes (OPCs), the glial cells of the central nervous system which after maturation are responsible for axon myelination. In accordance with the requirement for Hedgehog signaling in ventral patterning, the earliest identifiable cells in the oligodendrocyte lineage are derived from the ventral ventricular zone of the developing spinal cord and brain. Here, we present the current knowledge about the involvement of Hedgehog signaling in the strict spatial and temporal regulation which characterizes the initiation and progression of the oligodendrocyte lineage. We notably describe the ability of the Hedgehog signaling to tightly orchestrate the appearance of specific combinations of genes in concert with other pathways. We document the molecular mechanisms controlling Hedgehog temporal activity during OPC specification. The contribution of the pathway to aspects of OPC development different from their specification is also highlighted especially in the optic nerve. Finally, we report the data demonstrating that Hedgehog signaling-dependency is not a universal situation for oligodendrocyte generation as evidenced in the dorsal spinal cord in contrast to the dorsal forebrain.
Highlights
Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS)
The high increase in O4+ cells induced by the artificial rise in the concentration of Sonic hedgehog (Shh) (25–100 nM compared to 2–25 to classically induce motor neurons (MNs)) in the early E1.5 chick neural tube led to propose that the accumulation of the Shh protein at the surface of the ventral neural progenitors is a decisive step in the MN/OL transition [29]
Hedgehog signaling involvement in OL progenitor cells (OPCs) production is conserved across vertebrates including human and regards the whole CNS
Summary
Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). Contrasting with the wide distribution of OLs in the mature CNS, OL progenitor cells (OPCs) originate at early stages of development in restricted sites bordering the cerebral ventricles and spinal canal before they subsequently migrate into adjacent regions. OPCs express a characteristic set of markers, including the platelet-derived growth factor receptor alpha (Pdgfrα) and the neuron/glial antigen 2 (NG2) proteoglycan Both markers are rapidly downregulated when the cells differentiate into OLs, unlike other lineage markers as the transcription factors SRY-Box (Sox) 10 and Olig, which are expressed in both OPCs and OLs. The mature OLs can be identified by their expression of adenomatous polyposis coli (APC) and the myelin basic protein (Mbp), among others (Figure 1). At early stages of neurogenesis, the potential of these primary progenitors becomes regionally restricted through the activity of organizing signals The latter involve gradients of secreted proteins such as Hedgehog and BMP/Wnt proteins, J.
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