Abstract
BackgroundMost oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2. A minority of oligodendrocytes is also recognized to emerge from dorsal progenitors during fetal development. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs).ResultsUsing the well-established model of the chicken embryo, we show that ventral spinal progenitor cells activate FGF signaling at the onset of oligodendrocyte precursor cell (OPC) generation. Inhibition of FGF receptors at that time appears sufficient to prevent generation of ventral OPCs, highlighting that, in addition to Shh, FGF signaling is required also for generation of ventral OPCs. We further reveal an unsuspected interplay between Shh and FGF signaling by showing that FGFs serve dual essential functions in ventral OPC specification. FGFs are responsible for timely induction of a secondary Shh signaling center, the lateral floor plate, a crucial step to create the burst of Shh required for OPC specification. At the same time, FGFs prevent down-regulation of Olig2 in pMN progenitor cells as these cells receive higher threshold of the Shh signal. Finally, we bring arguments favoring a key role of newly differentiated neurons acting as providers of the FGF signal required to trigger OPC generation in the ventral spinal cord.ConclusionAltogether our data reveal that the FGF signaling pathway is activated and required for OPC commitment in the ventral spinal cord. More generally, our data may prove important in defining strategies to produce large populations of determined oligodendrocyte precursor cells from undetermined neural progenitors, including stem cells. In the long run, these new data could be useful in attempts to stimulate the oligodendrocyte fate in residing neural stem cells.
Highlights
Most oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2
Using chicken as a well-established model of oligodendrocyte precursor cell (OPC) development, we provide evidence for a dual role of Fibroblast growth factor (FGF) signaling acting upstream of Sonic hedgehog (Shh) to promote induction of the lateral floor plate (LFP) and together with Shh to ensure maintenance of Olig2 expression in pMN progenitor cells as they activate Nkx2.2 in response to high threshold Shh signal
MAPK signaling is activated at initiation of OPC commitment in the ventral spinal cord Previous studies have reported that FGFs can induce production of OPCs from dorsal spinal cord and cerebral cortex progenitor cells [1, 9, 13, 14, 31, 40, 53]
Summary
Most oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs). The second phase of OPC generation from dorsal progenitor cells occurs independently of Shh and has been proposed instead to depend on Fibroblast growth factors (FGFs) that have been proposed to act by counteracting BMP signaling [9, 14, 40, 80]. Contrasting with the proposed model for the spinal cord, ventral OPC generation in the developing brain depends on a Shh and FGF interplay, whose precise mechanism remains, to be elucidated
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