Genomic integration of Wnt/b-catenin and BMP/Smad1 coordinates the transcriptional program of foregut and hindgut progenitors
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ABSTRACT:
ORGANISM(S): Xenopus laevis
PROVIDER: GSE87654 | GEO | 2017/02/28
SECONDARY ACCESSION(S): PRJNA345481
REPOSITORIES: GEO
Similar Datasets
Project description:Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are interpreted in the genome is poorly understood. Here we identified the transcriptomes of Xenopus foregut and hindgut progenitors, which are conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/β-catenin acts as a genome-wide toggle between foregut and hindgut programs. Unexpectedly, β-catenin and Smad1 binding were associated with both transcriptional activation and repression, with Wnt-repressed genes often lacking canonical Tcf DNA binding motifs, suggesting a novel mode of direct repression. Combinatorial Wnt and BMP signaling was mediated by Smad1 and β-catenin co-occupying hundreds of cis-regulatory DNA elements, and by a crosstalk whereby Wnt negatively regulates BMP ligand expression in the foregut. These results extend our understanding of gastrointestinal organogenesis and of how Wnt and BMP might coordinate genomic responses in other contexts.
| S-EPMC5399627 | biostudies-literature
Project description:Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how they are integrated in the genome is poorly understood. Here we identified the Xenopus foregut and hindgut progenitor transcriptomes, which are largely conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/b-catenin acts as a genome-wide toggle between foregut and hindgut programs. In addition to b-catenin-Tcf promoting hindgut gene transcription, we unexpectedly observed Wnt-repressed foregut genes associated with b-catenin-binding to DNA lacking Tcf motifs, suggesting a novel direct repression. We define how BMP and Wnt signaling are integrated in the genome with Smad1 and β-catenin co-occupying DNA elements associated with hundreds of key regulatory genes. These results extend our understanding of GI organogenesis and how Wnt and BMP may coordinate genomic responses in other contexts.
2017-02-28 | GSE87653 | GEO
Project description:Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how they are integrated in the genome is poorly understood. Here we identified the Xenopus foregut and hindgut progenitor transcriptomes, which are largely conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/b-catenin acts as a genome-wide toggle between foregut and hindgut programs. In addition to b-catenin-Tcf promoting hindgut gene transcription, we unexpectedly observed Wnt-repressed foregut genes associated with b-catenin-binding to DNA lacking Tcf motifs, suggesting a novel direct repression. We define how BMP and Wnt signaling are integrated in the genome with Smad1 and β-catenin co-occupying DNA elements associated with hundreds of key regulatory genes. These results extend our understanding of GI organogenesis and how Wnt and BMP may coordinate genomic responses in other contexts.
2017-02-28 | GSE87652 | GEO
Project description:Genomic integration of Wnt/b-catenin and BMP/Smad1 coordinates the transcriptional program of foregut and hindgut progenitors
| PRJNA345481 | ENA
Project description:Temporally and spatially dynamic Wnt and BMP signals are essential to pattern foregut endoderm progenitors that give rise to the liver, pancreas and lungs, but how these two signaling pathways are coordinated in the extracellular space is unknown. Here we identify the transmembrane heparan sulphate proteoglycan Syndecan-4 (Sdc4), as a key regulator of both non-canonical Wnt and BMP signaling in the Xenopus foregut. Foregut-specific Sdc4 depletion results in a disrupted Fibronectin (Fn1) matrix, reduced cell adhesion, and failure to maintain foregut gene expression ultimately leading to foregut organ hypoplasia. Sdc4 is required to maintain robust Wnt/JNK and BMP/Smad1 signaling in the hhex+ foregut progenitors. Pathway analysis suggests that Sdc4 functionally interacts with Fzd7 to promote Wnt/JNK signaling, which maintains foregut identity and cell adhesion. In addition, the Sdc4 ectodomain is required to support Fn1 matrix assembly, which is essential for the robust BMP signaling that promotes foregut gene expression. This work sheds lights on how the extracellular matrix can coordinate different signaling pathways during organogenesis.
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Project description:Bone morphogenetic protein 9 (BMP-9) is a member of the transforming growth factor (TGF)-beta/BMP superfamily, and we have demonstrated that it is one of the most potent BMPs to induce osteoblast differentiation of mesenchymal stem cells (MSCs). Here, we sought to investigate if canonical Wnt/beta-catenin signalling plays an important role in BMP-9-induced osteogenic differentiation of MSCs. Wnt3A and BMP-9 enhanced each other's ability to induce alkaline phosphatase (ALP) in MSCs and mouse embryonic fibroblasts (MEFs). Wnt antagonist FrzB was shown to inhibit BMP-9-induced ALP activity more effectively than Dkk1, whereas a secreted form of LPR-5 or low-density lipoprotein receptor-related protein (LRP)-6 exerted no inhibitory effect on BMP-9-induced ALP activity. beta-Catenin knockdown in MSCs and MEFs diminished BMP-9-induced ALP activity, and led to a decrease in BMP-9-induced osteocalcin reporter activity and BMP-9-induced expression of late osteogenic markers. Furthermore, beta-catenin knockdown or FrzB overexpression inhibited BMP-9-induced mineralization in vitro and ectopic bone formation in vivo, resulting in immature osteogenesis and the formation of chondrogenic matrix. Chromatin immunoprecipitation (ChIP) analysis indicated that BMP-9 induced recruitment of both Runx2 and beta-catenin to the osteocalcin promoter. Thus, we have demonstrated that canonical Wnt signalling, possibly through interactions between beta-catenin and Runx2, plays an important role in BMP-9-induced osteogenic differentiation of MSCs.
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Project description:The liver, pancreas, and lungs are induced from endoderm progenitors by a series of dynamic growth factor signals from the mesoderm, but how the temporal-spatial activity of these signals is controlled is poorly understood. We have identified an extracellular regulatory loop required for robust bone morphogenetic protein (BMP) signaling in the Xenopus foregut. We show that BMP signaling is required to maintain foregut progenitors and induce expression of the secreted frizzled related protein Sizzled (Szl) and the extracellular metalloprotease Tolloid-like 1 (Tll1). Szl negatively regulates Tll activity to control deposition of a fibronectin (FN) matrix between the mesoderm and endoderm, which is required to maintain BMP signaling. Foregut-specific Szl depletion results in a loss of the FN matrix and failure to maintain robust pSmad1 levels, causing a loss of foregut gene expression and organ agenesis. These results have implications for BMP signaling in diverse contexts and the differentiation of foregut tissue from stem cells.
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Project description:BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.
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Project description:Bone morphogenetic protein 4 (Bmp4) is essential for lung development. To define the intracellular signaling mechanisms by which Bmp4 regulates lung development, BMP-specific Smad1 or Smad5 was selectively knocked out in fetal mouse lung epithelial cells. Abrogation of lung epithelial-specific Smad1, but not Smad5, resulted in retardation of lung branching morphogenesis and reduced sacculation, accompanied by altered distal lung epithelial cell proliferation and differentiation and, consequently, severe neonatal respiratory failure. By combining cDNA microarray with ChIP-chip analyses, Wnt inhibitory factor 1 (Wif1) was identified as a novel target gene of Smad1 in the developing mouse lung epithelial cells. Loss of Smad1 transcriptional activation of Wif1 was associated with reduced Wif1 expression and increased Wnt/?-catenin signaling activity in lung epithelia, resulting in specific fetal lung abnormalities. This suggests a novel regulatory loop of Bmp4-Smad1-Wif1-Wnt/?-catenin in coordinating BMP and Wnt pathways to control fetal lung development.
| S-EPMC3035095 | biostudies-literature
Project description:Patterning of the primitive foregut promotes appropriate organ specification along its anterior-posterior axis. However, the molecular pathways specifying foregut endoderm progenitors are poorly understood. We show here that Wnt2/2b signaling is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b expression exhibit complete lung agenesis and do not express Nkx2.1, the earliest marker of the lung endoderm. In contrast, other foregut endoderm-derived organs, including the thyroid, liver, and pancreas, are correctly specified. The phenotype observed is recapitulated by an endoderm-restricted deletion of beta-catenin, demonstrating that Wnt2/2b signaling through the canonical Wnt pathway is required to specify lung endoderm progenitors within the foregut. Moreover, activation of canonical Wnt/beta-catenin signaling results in the reprogramming of esophagus and stomach endoderm to a lung endoderm progenitor fate. Together, these data reveal that canonical Wnt2/2b signaling is required for the specification of lung endoderm progenitors in the developing foregut.
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