Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL-ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.
Pubmed ID: 31171630 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on May 5,2022.Tool that predicts interactions between transcription factors and their regulated genes from binding motifs. Understanding vertebrate development requires unraveling the cis-regulatory architecture of gene regulation. PRISM provides accurate genome-wide computational predictions of transcription factor binding sites for the human and mouse genomes, and integrates the predictions with GREAT to provide functional biological context. Together, accurate computational binding site prediction and GREAT produce for each transcription factor: 1. putative binding sites, 2. putative target genes, 3. putative biological roles of the transcription factor, and 4. putative cis-regulatory elements through which the factor regulates each target in each functional role.
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