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PMID:20713518

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Citation

Zhang, Y, Li, S, Yuan, L, Tian, Y, Weidenfeld, J, Yang, J, Liu, F, Chokas, AL and Morrisey, EE (2010) Foxp1 coordinates cardiomyocyte proliferation through both cell-autonomous and nonautonomous mechanisms. Genes Dev. 24:1746-57

Abstract

Cardiomyocyte proliferation is high in early development and decreases progressively with gestation, resulting in the lack of a robust cardiomyocyte proliferative response in the adult heart after injury. Little is understood about how both cell-autonomous and nonautonomous signals are integrated to regulate the balance of cardiomyocyte proliferation during development. In this study, we show that a single transcription factor, Foxp1, can control the balance of cardiomyocyte proliferation during development by targeting different pathways in the endocardium and myocardium. Endocardial loss of Foxp1 results in decreased Fgf3/Fgf16/Fgf17/Fgf20 expression in the heart, leading to reduced cardiomyocyte proliferation. This loss of myocardial proliferation can be rescued by exogenous Fgf20, and is mediated, in part, by Foxp1 repression of Sox17. In contrast, myocardial-specific loss of Foxp1 results in increased cardiomyocyte proliferation and decreased differentiation, leading to increased myocardial mass and neonatal demise. We show that Nkx2.5 is a direct target of Foxp1 repression, and Nkx2.5 expression is increased in Foxp1-deficient myocardium. Moreover, transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass, similar to the myocardial-specific loss of Foxp1. These data show that Foxp1 coordinates the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation of Fgf ligand and Nkx2.5 expression.

Links

PubMed PMC2922503 Online version:10.1101/gad.1929210

Keywords

Alleles; Animals; Cell Proliferation; Embryo, Mammalian; Fibroblast Growth Factors/metabolism; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Gene Deletion; Gene Expression Regulation, Developmental; HMGB Proteins/metabolism; Homeodomain Proteins/metabolism; Mice; Models, Biological; Myocardium/cytology; Myocardium/metabolism; Myocardium/pathology; Myocytes, Cardiac/cytology; Repressor Proteins/genetics; Repressor Proteins/metabolism; SOXF Transcription Factors/metabolism; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EOMES

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:EOMES

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NKX25

acts_upstream_of_or_within

GO:0060043: regulation of cardiac muscle cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NKX25

acts_upstream_of_or_within

GO:0045214: sarcomere organization

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1914004

P

Seeded From UniProt

complete

MOUSE:NKX25

acts_upstream_of_or_within

GO:0072359: circulatory system development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1914004

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4829787

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(MGI:MGI:107543)|has_input:(MGI:MGI:97350)

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0007507: heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4829787

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0060043: regulation of cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0060043: regulation of cardiac muscle cell proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1891346

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0055007: cardiac muscle cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4829787

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4829787

P

  • regulates_o_occurs_in:(EMAPA:32686)

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0045214: sarcomere organization

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97350

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0072359: circulatory system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4829787

P

Seeded From UniProt

complete

MOUSE:FOXP1

acts_upstream_of_or_within

GO:0072359: circulatory system development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97350

P

Seeded From UniProt

complete

HUMAN:PO5F1

acts_upstream_of_or_within

GO:0001714: endodermal cell fate specification

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FGF20

acts_upstream_of_or_within

GO:0060043: regulation of cardiac muscle cell proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1914004

P

Seeded From UniProt

complete

HUMAN:NANOG

acts_upstream_of_or_within

GO:0001714: endodermal cell fate specification

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NANOG

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

involved_in

GO:0001714: endodermal cell fate specification

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PO5F1

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SOX2

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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