Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells.
Progenitor cells of the first and second heart fields depend on cardiac-specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiac-specific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/β-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/β-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development.
Department of Cancer Research, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany.
Alexandra
A
Klaus
Marion
M
Müller
Herbert
H
Schulz
Yumiko
Y
Saga
James F
JF
Martin
Walter
W
Birchmeier
D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007763:Lac Operon; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D011247:Pregnancy; D051880:Receptors, Notch / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
D060466:Axin Protein; C111729:Axin2 protein, mouse; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C495267:CTNNB1 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C484469:Nkx2-5 protein, mouse; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C494055:Smarcd3 protein, mouse; D014157:Transcription Factors; D051176:beta Catenin; C063843:insulin gene enhancer binding protein Isl-1