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First published online 22 March 2006
doi: 10.1242/dev.02344

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Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse

Yusuke Watanabe^1,*,, Hiroki Kokubo^1,2,*, Sachiko Miyagawa-Tomita³, Maho Endo¹, Katsuhide Igarashi⁴, Ken ichi Aisaki⁴, Jun Kanno⁴ and Yumiko Saga^1,2,

¹ Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima 411-8540, Japan.
² Department of Genetics, The Graduate University for Advanced studies, Yata 1111, Mishima 411-8540, Japan.
³ Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjyuku-ku Tokyo162-8666, Japan.
⁴ Cellular and Molecular Toxicology Division, National Institute of Health Sciences, 1-18-1 Kamiyohga, Setagaya-ku Tokyo 158-8501, Japan.

Author for correspondence (e-mail: ysaga{at}lab.nig.ac.jp)

Accepted 23 February 2006

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.

Key words: Notch signaling, Heart formation, AV cushion, EMT

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