Procollagen IIA regulates BMP/TGFb signaling in patterning the heart and its major vessels

Bone morphogenetic proteins (BMPs) and transforming growth factors (TGFbs) play critical roles in the morphogenesis of the cardiovascular system. The level of signaling activity by BMPs/TGFbs perceived by the cells can be modulated by proteins which bind and sequester these morphogenetic factors in the extracellular space. Type II collagen is a wellknown structural component in the cartilage extracellular matrix (ECM) which is synthesized as a procollagen precursor, type IIB, by mature chondrocytes. Type IIA procollagen (IIA), an isoform of type II procollagen, is found preferentially in non-chondrogenic tissues such as the heart in early mouse and human embryos. IIA procollagen has been proposed to function as an antagonist of BMP/TGFb signaling in view of its ability to bind BMP/TGFb in in vitro assays and because ectopic expression of IIA can induce a secondary axis in Xenopus embryos. Mice that lack IIA die perinatally and displayed cardiac defects similar to those associated with human complex congenital heart diseases. IIAK/K newborns displayed interventricular septal defects, incomplete transposition of great arteries and double-outlet right ventricle. During development IIAK/K mutants exhibited incomplete heart looping and endocardial cushion defects. Early vascular symmetry was lost and patterning and remodelling of the branchial arch arteries were abnormal, suggesting that IIA may play an important role in maintaining left–right asymmetry. Several molecular indicators of BMP/TGFb signaling were reduced in the IIAK/K mutant heart. Our findings suggest IIA procollagen has a morphogenetic role, and regulates the patterning of the heart and major vessels by facilitating BMP/TGFb signaling. Supported by RGC7275/00M.link_to_subscribed_fulltex