A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice

TGFβ family members are implicated in cardiac organogenesis, growth control, and positional information, including the direction of cardiac 1ooping. However, genetic analysis of TGFβ signaling in mice has been confounded, in some cases, by noncardiac and generalized defects. Hence, deciphering TGFβ function in myocardium would benefit from cardiacrestricted mutations. We developed a constitutively activated type I receptor, ALK5(L193A, P194A, T204D), and directed it to embryonic myocardium in transgenic mice. Expression of the activated ALK5 gene arrests 1ooping 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 1ooping, perhaps through control of cardiac myocyte proliferation.