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Molecular and Cellular Biology, March 2005, p. 2191-2199, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2191-2199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Congenital Semilunar Valvulogenesis Defect in Mice Deficient in Phospholipase C{varepsilon}{dagger}

Makoto Tadano,1,{ddagger} Hironori Edamatsu,1,{ddagger} Susumu Minamisawa,2 Utako Yokoyama,2 Yoshihiro Ishikawa,2 Noboru Suzuki,3 Hiromitsu Saito,3 Dongmei Wu,1 Misa Masago-Toda,1 Yuriko Yamawaki-Kataoka,1 Tomiyoshi Setsu,4 Toshio Terashima,4 Sakan Maeda,5 Takaya Satoh,1 and Tohru Kataoka1*

Division of Molecular Biology, Department of Molecular and Cellular Biology,1 Division of Developmental Neurobiology, Department of Brain Sciences,4 Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe,5 Department of Physiology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama,2 Department of Animal Genomics, Functional Genomics Institute, Mie University Life Science Research Center, Tsu-shi, Mie, Japan3

Received 1 September 2004/ Returned for modification 18 October 2004/ Accepted 9 December 2004

Phospholipase C{varepsilon} is a novel class of phosphoinositide-specific phospholipase C, identified as a downstream effector of Ras and Rap small GTPases. We report here the first genetic analysis of its physiological function with mice whose phospholipase C{varepsilon} is catalytically inactivated by gene targeting. The hearts of mice homozygous for the targeted allele develop congenital malformations of both the aortic and pulmonary valves, which cause a moderate to severe degree of regurgitation with mild stenosis and result in ventricular dilation. The malformation involves marked thickening of the valve leaflets, which seems to be caused by a defect in valve remodeling at the late stages of semilunar valvulogenesis. This phenotype has a remarkable resemblance to that of mice carrying an attenuated epidermal growth factor receptor or deficient in heparin-binding epidermal growth factor-like growth factor. Smad1/5/8, which is implicated in proliferation of the valve cells downstream of bone morphogenetic protein, shows aberrant activation at the margin of the developing semilunar valve tissues in embryos deficient in phospholipase C{varepsilon}. These results suggest a crucial role of phospholipase C{varepsilon} downstream of the epidermal growth factor receptor in controlling semilunar valvulogenesis through inhibition of bone morphogenetic protein signaling.

* Corresponding author. Mailing address: Division of Molecular Biology, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5380. Fax: 81-78-382-5399. E-mail: kataoka{at}kobe-u.ac.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} M.T. and H.E. contributed equally to this work.

Molecular and Cellular Biology, March 2005, p. 2191-2199, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2191-2199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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