BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4
| Autor: | Orit Wolstein, Christine Biben, Sally L. Dunwoodie, Milena B. Furtado, Jost I. Preis, Yumiko Saga, Mauro W. Costa, Mark J. Solloway, Richard P. Harvey, Vanessa Jones, Patrick P.L. Tam, Elizabeth J. Robertson, Duncan B. Sparrow |
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| Rok vydání: | 2008 |
| Předmět: |
Mesoderm
animal structures Nodal Protein Nodal signaling Bone morphogenetic protein Cell Line Smad1 Protein Mice Gene expression Genetics medicine Animals Humans Body Patterning Smad4 Protein biology Lateral plate mesoderm Forkhead Transcription Factors Transforming growth factor beta Anatomy Cell biology medicine.anatomical_structure Bone Morphogenetic Proteins Mutation embryonic structures biology.protein Signal transduction NODAL Signal Transduction Research Paper Developmental Biology |
| Zdroj: | Genes & Development. 22:3037-3049 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.1682108 |
| Popis: | Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor β (TGFβ) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4–FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system. |
| Databáze: | OpenAIRE |
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