A CONSTITUTIVE MUTATION OF ALK5 DISRUPTS CARDIAC LOOPING AND MORPHOGENESIS IN MICE

TGF beta family members are implicated in cardiac organogenesis, growt h control, and positional information, including the direction of card iac looping. However, genetic analysis of TGF beta signaling in mice h as been confounded, in some eases, by noncardiac and generalized defec ts. Hence, deciphering TGF beta function in myocardium would benefit f rom cardiac-restricted mutations. We developed a constitutively activa ted type I receptor, ALK5(L193A,P194A,T204D) and directed it to embryo nic myocardium in transgenic mice. Expression of the activated ALK5 ge ne arrests looping morphogenesis and causes a Linear, dilated, hypopla stic heart tube, despite normal expression of Nkx2.5 and dHAND, cardio genic transcription factors whose absence provokes a similar phenotype . Ventricular hypoplasia was associated with precocious induction of t he cyclin-dependent kinase inhibitor, p21. Thus, an ALK5-sensitive pat hway mediates looping, perhaps through control of cardiac myocyte prol iferation. (C) 1998 Academic Press .