(6,27) Interestingly in the present study, we found that 9-cis-RA inhibited the Notch signaling pathway in the OPC lineage cells by downregulating the HES5 gene, while it exerted no effect on the Wnt signaling pathway.
(33) used RNA sequencing and showed that long-term in vitro treatment with 9-cis and all-trans RA increased the expression of the negative regulators of oligodendrocyte differentiation such as HES5. Furthermore, Green and colleagues (34) demonstrated that the use of RA receptor agonists in osteogenic cultures was able to augment the expression of the Wnt antagonist, secreted frizzled-related protein 4, and ultimately lead to the inhibition of this signaling pathway.
Based on our results, 1,25[(OH).sub.2][D.sub.3] has no effect on the expression level of the HES5 gene and, therefore, the Notch signaling pathway.
Moreover, 9-cis-RA suppressed the Notch signaling pathway via the downregulation of the HES5 gene, while 1,25[(OH).sub.2][D.sub.3] inhibited the Wnt signaling pathways via the downregulation of the LRP6 gene.
* 9-cis-retinoic acid and 1,25[(OH).sub.2][D.sub.3] inhibit the Notch and Wnt signaling pathways through the downregulation of the HES5 transcription factor and the LRP6 co-receptor, respectively.
Wnt3a could upregulate the downstream target gene Hes1 of the Notch signaling pathway and continue to inhibit the expression of Hes5, improve the level of Mash1, and then induce the proliferation of NSCs.
Frech, "HES5 is a key mediator of Wnt-3a-induced neuronal differentiation," Stem Cells and Development, vol.
(a) Wnt3a could upregulate the expression of the downstream target gene Hes1 of the Notch signaling pathway and inhibit the expression of Hes5 and then induce the proliferation of NSCs (the red arrows).