Myocardial Mycn is essential for mouse ventricular wall morphogenesis.
MYCN is a highly conserved transcription factor with multifaceted roles in development and disease. Mutations in MYCN are associated with Feingold syndrome, a developmental disorder characterized in part by congenital heart defects. Mouse models have helped elucidate MYCN functions; however its cardiac-specific roles during development remain unclear. We employed a Cre/loxp strategy to uncover the specific activities of MYCN in the developing mouse myocardium. Myocardial deletion of Mycn resulted in a thin-myocardial wall defect with dramatically reduced trabeculation. The mutant heart defects strongly resemble the phenotype caused by disruption of BMP10 and Neuregulin-1 (NRG1) signaling pathways, two central mediators of myocardial wall development. Our further examination showed that expression of MYCN is regulated by both BMP and NRG1 signaling. The thin-wall defect in mutant hearts is caused by a reduction in both cell proliferation and cell size. MYCN promotes cardiomyocyte proliferation through regulating expression of cell cycle regulators (including CCND1, CCND2, and ID2) and promotes cardiomyocyte growth through regulating expression of p70S6K. In addition, expression of multiple sarcomere proteins is altered in Mycn myocardial-inactivation embryos, indicating its essential role for proper cardiomyocyte differentiation. In summary, Mycn acts downstream of BMP and NRG1 cardiogenic signaling pathways to promote normal myocardial wall morphogenesis.
Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Cristina
C
Harmelink
Yin
Y
Peng
Paige
P
DeBenedittis
Hanying
H
Chen
Weinian
W
Shou
Kai
K
Jiao
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006352:Heart Ventricles / Q000196:embryology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D020890:Neuregulin-1 / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D017931:DNA Primers; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011518:Proto-Oncogene Proteins