Abstract
The proper function of the bone morphogenic protein (BMP) pathway during embryonic development and organ maintenance requires its communication with other signaling pathways. Unlike the well-documented regulation of the BMP pathway by FGF/MAPK and Wnt/GSK3 signals, cross-talk between BMP/Smad and retinoic acid (RA)/RA receptor (RAR) pathways is poorly understood. Here, we show that RA represses BMP signal duration by reducing the level of phosphorylated Smad1 (pSmad1). Through its nuclear receptor-mediated transcription, RA enhances the interaction between pSmad1 and its ubiquitin E3 ligases, thereby promoting pSmad1 ubiquitination and proteasomal degradation. This regulation depends on the RA-increased Gadd45 expression and MAPK activation. During the neural development in chicken embryo, the RA/RAR pathway also suppresses BMP signaling to antagonize BMP-regulated proliferation and differentiation of neural progenitor cells. Furthermore, this cross-talk between RA and BMP pathways is involved in the proper patterning of dorsal neural tube of chicken embryo. Our results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Differentiation / physiology
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Cell Line, Tumor
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Cell Proliferation
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Chick Embryo
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Embryonic Development / physiology
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / metabolism
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Mice
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Neural Tube / embryology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphorylation / physiology
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Signal Transduction / physiology*
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Smad1 Protein / genetics
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Smad1 Protein / metabolism*
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Stem Cells / metabolism
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Tretinoin / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / physiology*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
Substances
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Bone Morphogenetic Proteins
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Cell Cycle Proteins
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Gadd45a protein, mouse
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Nuclear Proteins
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Receptors, Retinoic Acid
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Smad1 Protein
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Smad1 protein, mouse
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Wnt Proteins
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Tretinoin
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Epidermal Growth Factor
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Ubiquitin-Protein Ligases
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Glycogen Synthase Kinase 3
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Mitogen-Activated Protein Kinase Kinases
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Proteasome Endopeptidase Complex