Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor- (TGF) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre͞lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGF2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis.
Bone morphogenetic proteins (BMPs), named for their firstdiscovered role in bone differentiation, mediate a diverse spectrum of developmental events, such as dorsal-ventral patterning, mesoderm specification, and the spacing of embryo implantation (1, 2). BMPs are postulated to mediate cardiac development in mammals, by extrapolation from the role of decapentaplegic, a related factor in Drosophila (3), their function in cardiac looping in fish (4) or frogs (5), and, especially, studies of cardiac myogenesis in avians (6, 7). Avian explant studies also implicate BMPs as an essential paracrine signal from myocardium adjacent to the endocardial cushion during the epithelialmesenchymal transformation and later events that ultimately give rise to the atrio-ventricular (AV) valves (8). This process is known to involve TGF2 and TGF3 as well (9-12), but the molecular connection between BMPs and TGF is uncertain.Despite inferences from the distribution of BMPs during heart formation (13), and BMP effects on cardiac differentiation in teratocarcinoma cells (14), evidence analogous to that for other species is lacking in mammals themselves. One barrier to using conventional germline deletions to resolve these issues in mice is the greater potential for redundancy among BMP family members than in flies. In the mid-gestation heart, BMP2 and -4 are found, respectively, in myocardial layers of the AV canal and in the AV cushion itself, BMP5, -6, and -7 are initially homogeneous throughout the myocardium, and BMP10, which is heart-specific, is found exclusively in trabeculae (14,15). This diversity, with overlapping and nonoverlapping programs of expression, suggests the utility of addressing the question via BMP receptors, instead, which are smaller in number.BMPs bind two serine͞threonine kinase receptors, type II (BMPRII) and type I (ALK3͞BMPR-IA and ALK6͞BMPR-IB), which form a heteromeric signaling complex acting in series, as for other TGF family receptors (16). In the presence of ligand, the type II receptor phosphorylates the type I receptors, which activate signaling by intracellular effectors including Smad transcription factors (16). ALK3 is ubiquitous throughout development, wherea...