Abstract
Shared molecular programs govern the formation of heart and head during mammalian embryogenesis. Development of both structures is disrupted in human chromosomal microdeletion of 22q11.2 (del22q11), which causes DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). Here, we have identified a genetic pathway involving the Six1/Eya1 transcription complex that regulates cardiovascular and craniofacial development. We demonstrate that murine mutation of both Six1 and Eya1 recapitulated most features of human del22q11 syndromes, including craniofacial, cardiac outflow tract, and aortic arch malformations. The mutant phenotypes were attributable in part to a reduction of fibroblast growth factor 8 (Fgf8), which was shown to be a direct downstream effector of Six1 and Eya1. Furthermore, we showed that Six1 and Eya1 genetically interacted with Fgf8 and the critical del22q11 gene T-box transcription factor 1 (Tbx1) in mice. Together, these findings reveal a Tbx1-Six1/Eya1-Fgf8 genetic pathway that is crucial for mammalian cardiocraniofacial morphogenesis and provide insights into the pathogenesis of human del22q11 syndromes.
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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Animals
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Base Sequence
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Cardiovascular Abnormalities / genetics
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Cardiovascular System / embryology*
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Cell Proliferation
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Cell Survival / genetics
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Chromosomes, Human, Pair 22 / genetics
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Craniofacial Abnormalities / genetics
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DNA Primers / genetics
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DiGeorge Syndrome / genetics
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Disease Models, Animal
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Facial Bones / embryology*
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Fibroblast Growth Factor 8 / deficiency
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Fibroblast Growth Factor 8 / genetics*
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Homeodomain Proteins / genetics*
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Humans
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics*
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Mice
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Mice, 129 Strain
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Morphogenesis / genetics
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Mutation
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics*
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Protein Tyrosine Phosphatases / deficiency
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Protein Tyrosine Phosphatases / genetics*
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Skull / embryology*
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / genetics*
Substances
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DNA Primers
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Fgf8 protein, mouse
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Six1 protein, mouse
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T-Box Domain Proteins
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Tbx1 protein, mouse
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Fibroblast Growth Factor 8
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Eya1 protein, mouse
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Protein Tyrosine Phosphatases