Abstract
We have recently described a new subfamily of Fox genes, Foxp1/2/4, which are transcriptional repressors and are thought to regulate important aspects of development in several tissues, including the lung, brain, thymus and heart. Here, we show that Foxp1 is expressed in the myocardium as well as the endocardium of the developing heart. To further explore the role of Foxp1 in cardiac development, we inactivated Foxp1 through gene targeting in embryonic stem cells. Foxp1 mutant embryos have severe defects in cardiac morphogenesis, including outflow tract septation and cushion defects, a thin ventricular myocardial compact zone caused by defects in myocyte maturation and proliferation, and lack of proper ventricular septation. These defects lead to embryonic death at E14.5 and are similar to those observed in other mouse models of congenital heart disease, including Sox4 and Nfatc1 null embryos. Interestingly, expression of Sox4 in the outflow tract and cushions of Foxp1 null embryos is significantly reduced, while remodeling of the cushions is disrupted, as demonstrated by reduced apoptosis and persistent Nfatc1 expression in the cushion mesenchyme. Our results reveal a crucial role for Foxp1 in three aspects of cardiac development: (1) outflow tract development and septation, (2) tissue remodeling events required for cardiac cushion development, and (3) myocardial maturation and proliferation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation*
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Cell Division
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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Down-Regulation
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Embryo Loss / metabolism
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Embryo Loss / pathology
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Embryo, Mammalian / metabolism
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Embryo, Mammalian / pathology
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Endocardial Cushion Defects / embryology
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Endocardial Cushion Defects / metabolism*
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Endocardial Cushion Defects / pathology
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Endocardium / metabolism
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Endocardium / pathology
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Enzyme Inhibitors / pharmacology
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Forkhead Transcription Factors
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Gene Expression Regulation, Developmental
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Heart / drug effects
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Heart / embryology*
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Heart / physiology*
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Heart Diseases / congenital
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Heart Diseases / metabolism
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Heart Diseases / pathology
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High Mobility Group Proteins / genetics
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In Situ Hybridization
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Mice
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Mice, Knockout
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Morphogenesis*
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Muscle Cells / drug effects
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Muscle Cells / metabolism
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Muscle Cells / pathology*
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Myocardium / metabolism
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Myocardium / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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SOXC Transcription Factors
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Trans-Activators / genetics
Substances
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Enzyme Inhibitors
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FOXP1 protein, human
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Forkhead Transcription Factors
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Foxp1 protein, mouse
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High Mobility Group Proteins
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RNA, Messenger
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Repressor Proteins
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SOXC Transcription Factors
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Sox4 protein, mouse
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Trans-Activators
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Cyclin-Dependent Kinases