A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice.
TGF beta family members are implicated in cardiac organogenesis, growth control, and positional information, including the direction of cardiac looping. However, genetic analysis of TGF beta signaling in mice has been confounded, in some cases, by noncardiac and generalized defects. Hence, deciphering TGF beta function in myocardium would benefit from cardiac-restricted mutations. We developed a constitutively activated type I receptor, ALK5L193A,P194A,T204D, and directed it to embryonic myocardium in transgenic mice. Expression of the activated ALK5 gene arrests looping morphogenesis and causes a linear, dilated, hypoplastic heart tube, despite normal expression of Nkx2.5 and dHAND, cardiogenic transcription factors whose absence provokes a similar phenotype. Ventricular hypoplasia was associated with precocious induction of the cyclin-dependent kinase inhibitor, p21. Thus, an ALK5-sensitive pathway mediates looping, perhaps through control of cardiac myocyte proliferation.
Charng
M J
MJ
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Frenkel
P A
PA
Lin
Q
Q
Yamada
M
M
Schwartz
R J
RJ
Olson
E N
EN
Overbeek
P
P
Schneider
M D
MD
Yumada
M
M
D030201:Activin Receptors, Type I; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D006321:Heart / Q000196:embryology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D009154:Mutation; D009206:Myocardium / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins
D030201:Activin Receptors, Type I; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C493957:Cdkn1a protein, mouse; C498766:Hand2 protein, mouse; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C410915:hand2 protein, zebrafish; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse