FGF signaling controls Shh-dependent oligodendroglial fate specification in the ventral spinal cord

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.

Neuroepithelial organoid patterning is mediated by Wnt-driven Turing mechanism

“…Patterning in epithelial tissues rely on complex and dynamic signaling 4,39,49 . In the neural tube 28,34,43,44,48 , WNT 32,33 , BMP 34 , NOTCH 35,36 , FGF 37,38 and SHH 28 have been recognized as main modulators of patterning which orchestrate domain specification along the dorsoventral as well as anteroposterior axis. Once these morphogens establish a patterning reference frame, inter-domain signaling assist with domain boundary specification.…”

“…Once these morphogens establish a patterning reference frame, inter-domain signaling assist with domain boundary specification. For example, mediated by SHH, NKX2.2 in the p3 domain prevents the progression of the adjacent pMN domain through OLIG2 inhibition in the ventral NT 28,38 and in NTOs 9 . Moreover, intra-domain signaling is required for maintenance of cell identity, similar to the role of SHH in the FP 44 .…”

New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

“…The kinetics of RTK/ERK signaling is critical to its function, in that the apparently divergent effects of RTK/ERK signaling on proliferation versus differentiation are explained by the ability of Ngf/Ntrk1 to activate ERK in a sustained manner, whereas Fgf induces strong, transient ERK activation ( Marshall, 1995 ; York et al, 1998 ). Mechanistic insights have also been gained into how Fgf activation biases NPCs to acquire an oligodendrocyte fate, both in the telencephalon and spinal cord ( Gabay et al, 2003 ; Furusho et al, 2011 ; Li et al, 2014 ; Farreny et al, 2018 ), where Fgf acts in combination with Shh in an evolutionarily conserved manner ( Esain et al, 2010 ). Mechanistically, downstream activation of ERK directly phosphorylates Ascl1, and higher levels of RAS/ERK activation biases this proneural TF to preferentially transactivate glioblast genes instead of promoting a GABAergic neuronal identity ( Li et al, 2014 ).…”

Developmental and Repairing Production of Myelin: The Role of Hedgehog Signaling

“…Sulfatase2 coordinates its activity with sulfatase1 in this process ( Jiang et al, 2017 ). In addition, fibroblast growth factors (Fgfs) initially thought to influence the Hedgehog-independent generation of dorsal oligodendrocytes occuring 3 days after the generation of pMN-derived OPCs, also participates in the creation of the burst of Shh required for ventral OPC specification ( Farreny et al, 2018 ). In the zebrafish, sulfatase1 activity similarly stands as a timer activating neuronal and oligodendroglial generation at 14 and 36 h post-fertilization, respectively, in response to high concentrations of Hedgehog proteins ( Al Oustah et al, 2014 ).…”