Inhibition of FGF and TGF-β Pathways in hESCs Identify STOX2 as a Novel SMAD2/4 Cofactor

Abstract

The fibroblast growth factor (FGF) and the transforming growth factor-β (TGF-β) pathways are both involved in the maintenance of human embryonic stem cells (hESCs) and regulate the onset of their differentiation. Their converging functions have suggested that these pathways might share a wide range of overlapping targets. Published studies have focused on the long-term effects (24–48 h) of FGF and TGF-β inhibition in hESCs, identifying direct and indirect target genes. In this study, we focused on the earliest transcriptome changes occurring between 3 and 9 h after FGF and TGF-β inhibition to identify direct target genes only. Our analysis clearly shows that only a handful of target transcripts are common to both pathways. This is surprising in light of the previous literature, and has implications for models of cell signaling in human pluripotent cells. In addition, we identified STOX2 as a novel primary target of the TGF-β signaling pathway. We show that STOX2 might act as a novel SMAD2/4 cofactor. Taken together, our results provide insights into the effect of cell signaling on the transcription profile of human pluripotent cells

Nephron progenitors rhythmically alternate between renewal and differentiation phases that synchronize with kidney branching morphogenesis

“…S2 ). These hits together suggest possible differential regulation of retinoic acid ( Retsat ), Wnt/β-catenin ( Mucl1 ) 43 , TGFβ ( Stox2 ) 44 , and PI3K/Akt ( Mrps17 ) 45 signaling pathways in nephron progenitors over the branching life-cycle ( Note S1 ).…”

“…For example, Lef1 and Pax8 clustered together, both being upregulated around the transition from pre- to mid-branching and downregulated in post-branching niches. Several transcripts associated with FGF and TGFβ signaling peaked in mid-/post-branching ( Gas1 17,68,69 , Fgf1 10,47,48 , Fgfr1 47,48,70 , Stox2 44 , Tgfbi 47,51,71 ), and the YAP-dependent gene Traf1 19 along with Ttc28 , Retsat , and Mucl1 peaked in post-branching niches, continuing into pre-branching ones (formed as post-branching niches enter another round of branching), Fig. 4A , Fig.…”

Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes

“…The storkhead box-2 (STOX2) gene encodes a transcription factor that had been associated with pre-eclampsia and oral squamous carcinomas [ 27 , 28 ]. It functions as a SMAD2/4 cofactor [ 29 ], and its expression is regulated by the TGF-β signaling pathway, which also regulates LOX expression, and vice versa [ 30 , 31 ]. Anterior gradient 2 (AGR2) is a disulfide isomerase that participates in protein folding in the endoplasmic reticulum [ 32 ].…”