Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development.
Outflow tract (OFT) anomalies are among the most common congenital heart defects found at birth. The embryonic OFT grows by the progressive addition of cardiac progenitors, termed the second heart field (SHF), which originate from splanchnic pharyngeal mesoderm. Development of the SHF is controlled by multiple intercellular signals and transcription factors; however the relationship between different SHF regulators remains unclear. We have recently shown that Hoxa1 and Hoxb1 are expressed in a sub-population of the SHF contributing to the OFT. Here, we report that Hoxb1 deficiency results in a shorter OFT and ventricular septal defects (VSD). Mechanistically, we show that both FGF/ERK and BMP/SMAD signaling, which regulate proliferation and differentiation of cardiac progenitor cells and OFT morphogenesis, are enhanced in the pharyngeal region in Hoxb1 mutants. Absence of Hoxb1 also perturbed SHF development through premature myocardial differentiation. Hence, the positioning and remodeling of the mutant OFT is disrupted. Hoxa1(-/-) embryos, in contrast, have low percentage of VSD and normal SHF development. However, compound Hoxa1(-/-); Hoxb1(+/-) embryos display OFT defects associated with premature SHF differentiation, demonstrating redundant roles of these factors during OFT development. Our findings provide new insights into the gene regulatory network controlling SHF and OFT formation.
Aix Marseille Université, GMGF, 13385 Marseille, France; Inserm, UMR_S910, 13385 Marseille, France.
Marine
M
Roux
Aix Marseille Université, GMGF, 13385 Marseille, France; Inserm, UMR_S910, 13385 Marseille, France.
Brigitte
B
Laforest
Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA.
Mario
M
Capecchi
Aix Marseille Université, GMGF, 13385 Marseille, France; Inserm, UMR_S910, 13385 Marseille, France.
Nicolas
N
Bertrand
Aix Marseille Université, GMGF, 13385 Marseille, France; Inserm, UMR_S910, 13385 Marseille, France. Electronic address: stephane.zaffran@univ-amu.fr.
Stéphane
S
Zaffran
D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004622:Embryo, Mammalian; D005697:Galactosides; D005838:Genotype; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007211:Indoles; D008648:Mesoderm / Q000166:cytology*; D009024:Morphogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D000099261:Homeobox A1 Protein
D017931:DNA Primers; D005697:Galactosides; D018398:Homeodomain Proteins; D007211:Indoles; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
Congenital heart defect; Heart; Hox genes; Mouse; Second heart field