Analysis of the Effect of Fibulin-1 on Fibroblast Growth Factor 8 Signaling

ABSTRACT: We have previously shown that human fibulin-1 (FBLN1) is a binding partner of fibroblast growth factor 8 (FGF8) and affects its expression and signaling. Herein, we investigate the mechanisms by which FBLN1 affects FGF8 signaling. Fibulin-1 (Fbln1) -deficiency in mouse embryo fibroblasts (MEF) caused downregulation of Fgf8 as well as fibroblast growth factor receptors (Fgfr) 1 and 3 and several downstream genes in the Fgf8 pathway, including Six1, Eya1 and Barx1. The Fgf8-regulated putative DiGeorge syndrome gene, Tbx1, was also significantly downregulated. Fbln1-deficiency in MEFs caused upregulation of Sonic hedgehog (Shh), an established upstream regulator of Fgf8. Surprisingly, this was accompanied by downregulation of several Shh signaling pathway targets, including patched1, smoothened, Gli1 and Gli3. Analysis of Fbln1-null embryonic hindbrain and arch regions showed that Shh was upregulated in the 2nd arch but downregulated in arches 1, 3 and 4. A broader transcriptomic analysis of mouse hindbrain and arches confirmed that Fbln1 deficiency caused changes in the mitogen activated protein kinase (Mapk) and Wnt signaling pathways. Biochemical tests showed that Fbln1 binds to Shh and that its absence blocks secretion of Shh by MEFs. Based on these results, Fbln1 affects Fgf8 signaling by influencing expression of Shh and its downstream targets, including Mapk and Wnt signaling pathways. This affect may involve direct interaction of Fbln1 with Shh in a manner facilitating the production of secreted Shh.

ORGANISM(S): Mus musculus

PROVIDER: GSE102844 | GEO | 2019/08/16

REPOSITORIES: GEO