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PLoS One 2023 Jan 01;1810:e0286040. doi: 10.1371/journal.pone.0286040.
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Regulation of gene expression downstream of a novel Fgf/Erk pathway during Xenopus development.

Cowell LM , King M , West H , Broadsmith M , Genever P , Pownall ME , Isaacs HV .

Activation of Map kinase/Erk signalling downstream of fibroblast growth factor (Fgf) tyrosine kinase receptors regulates gene expression required for mesoderm induction and patterning of the anteroposterior axis during Xenopus development. We have proposed that a subset of Fgf target genes are activated in the embyo in response to inhibition of a transcriptional repressor. Here we investigate the hypothesis that Cic (Capicua), which was originally identified as a transcriptional repressor negatively regulated by receptor tyrosine kinase/Erk signalling in Drosophila, is involved in regulating Fgf target gene expression in Xenopus. We characterise Xenopus Cic and show that it is widely expressed in the embryo. Fgf overexpression or ectodermal wounding, both of which potently activate Erk, reduce Cic protein levels in embryonic cells. In keeping with our hypothesis, we show that Cic knockdown and Fgf overexpression have overlapping effects on embryo development and gene expression. Transcriptomic analysis identifies a cohort of genes that are up-regulated by Fgf overexpression and Cic knockdown. We investigate two of these genes as putative targets of the proposed Fgf/Erk/Cic axis: fos and rasl11b, which encode a leucine zipper transcription factor and a ras family GTPase, respectively. We identify Cic consensus binding sites in a highly conserved region of intron 1 in the fos gene and Cic sites in the upstream regions of several other Fgf/Cic co-regulated genes, including rasl11b. We show that expression of fos and rasl11b is blocked in the early mesoderm when Fgf and Erk signalling is inhibited. In addition, we show that fos and rasl11b expression is associated with the Fgf independent activation of Erk at the site of ectodermal wounding. Our data support a role for a Fgf/Erk/Cic axis in regulating a subset of Fgf target genes during gastrulation and is suggestive that Erk signalling is involved in regulating Cic target genes at the site of ectodermal wounding.

PubMed ID: 37856433
PMC ID: PMC10586617
Article link: PLoS One
Grant support: [+]

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: adamts1 arhgap11a.1 atf3 bcl2l11 cdx4 cic dusp6 egr1 etv1 etv4 evx1 fam83c fezf1 fezf2 fgf4 fos fosl1 foxg1 frzb gdf3 hoxa7 hoxb9 ier3 jun mapk1 mcf2 mix1 myc otx2 pax6 psmd6 rab20 rab7b rasl11b rax rgl2 ripply2.1 ripply2.2 six3 sox17b.1 spib tbxt wnt8a
GO keywords: MAP kinase activity [+]

Article Images: [+] show captions
References [+] :
Abaffy, The role of nitric oxide during embryonic wound healing. 2019, Pubmed, Xenbase