1. A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice
- Author
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Charng, Min-Ji, Frenkel, Peter A., Lin, Qing, Yumada, Miho, Schwartz, Robert J., Olson, Eric N., Overbeek, Paul, and Schneider, Michael D.
- Subjects
Mice -- Genetic aspects ,Gene mutations -- Research ,Heart -- Growth ,Morphogenesis -- Analysis ,Biological sciences - Abstract
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, [ALK5.sup.L193A,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. Key Words: ALK5; cardiac development; looping; p21; TGF[Beta].
- Published
- 1998