Abstract
Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may co-reside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Blotting, Western
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COUP Transcription Factor II / genetics
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COUP Transcription Factor II / metabolism*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cells, Cultured
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Down-Regulation
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Feedback, Physiological
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Gene Expression Profiling
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Models, Biological
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Oligonucleotide Array Sequence Analysis
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Protein Binding
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RNA Interference
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Signal Transduction
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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COUP Transcription Factor II
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Calcium-Binding Proteins
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Cell Cycle Proteins
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DLL4 protein, human
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HEY1 protein, human
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HEY2 protein, human
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptor, Notch1
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Repressor Proteins
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Serrate-Jagged Proteins
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Tumor Suppressor Proteins
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prospero-related homeobox 1 protein