Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse.
Notch signaling is implicated in many developmental processes. In our current study, we have employed a transgenic strategy to investigate the role of Notch signaling during cardiac development in the mouse. Cre recombinase-mediated Notch1 (NICD1) activation in the mesodermal cell lineage leads to abnormal heart morphogenesis, which is characterized by deformities of the ventricles and atrioventricular (AV) canal. The major defects observed include impaired ventricular myocardial differentiation, the ectopic appearance of cell masses in the AV cushion, the right-shifted interventricular septum (IVS) and impaired myocardium of the AV canal. However, the fates of the endocardium and myocardium were not disrupted in NICD1-activated hearts. One of the Notch target genes, Hesr1, was found to be strongly induced in both the ventricle and the AV canal of NICD1-activated hearts. However, a knockout of the Hesr1 gene from NICD-activated hearts rescues only the abnormality of the AV myocardium. We searched for additional possible targets of NICD1 activation by GeneChip analysis and found that Wnt2, Bmp6, jagged 1 and Tnni2 are strongly upregulated in NICD1-activated hearts, and that the activation of these genes was also observed in the absence of Hesr1. Our present study thus indicates that the Notch1 signaling pathway plays a suppressive role both in AV myocardial differentiation and the maturation of the ventricular myocardium.
Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540, Japan.
Yusuke
Y
Watanabe
Hiroki
H
Kokubo
Sachiko
S
Miyagawa-Tomita
Maho
M
Endo
Katsuhide
K
Igarashi
Ken ichi
Ki
Aisaki
Jun
J
Kanno
Yumiko
Y
Saga
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004627:Embryonic Induction / Q000235:genetics*; D004694:Endocardial Cushion Defects / Q000196:embryology; D006321:Heart / Q000196:embryology*; D006325:Heart Atria / Q000166:cytology / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006346:Heart Septum / Q000196:embryology; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology; D019426:Integrases; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D019426:Integrases; D051881:Receptor, Notch1; D012097:Repressor Proteins; D014764:Viral Proteins; C120420:Hey1 protein, mouse; C485778:Hey2 protein, mouse; C497762:Notch1 protein, mouse; C045073:Cre recombinase