Congenital semilunar valvulogenesis defect in mice deficient in phospholipase C epsilon.
Phospholipase Cepsilon 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 Cepsilon 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 Cepsilon. These results suggest a crucial role of phospholipase Cepsilon downstream of the epidermal growth factor receptor in controlling semilunar valvulogenesis through inhibition of bone morphogenetic protein signaling.
Tadano
Makoto
M
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.
Edamatsu
Hironori
H
Minamisawa
Susumu
S
Yokoyama
Utako
U
Ishikawa
Yoshihiro
Y
Suzuki
Noboru
N
Saito
Hiromitsu
H
Wu
Dongmei
D
Masago-Toda
Misa
M
Yamawaki-Kataoka
Yuriko
Y
Setsu
Tomiyoshi
T
Terashima
Toshio
T
Maeda
Sakan
S
Satoh
Takaya
T
Kataoka
Tohru
T
D000483:Alleles; D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000196:embryology* / Q000276:immunology; D001028:Aortopulmonary Septal Defect / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D006349:Heart Valve Diseases / Q000150:complications / Q000235:genetics; D006352:Heart Ventricles / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D054801:Phosphoinositide Phospholipase C; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011664:Pulmonary Valve / Q000002:abnormalities* / Q000196:embryology* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D010738:Type C Phospholipases / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D015534:Trans-Activators; D066246:ErbB Receptors; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon
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