UC San Diego

Cardiac morphogenesis and skeletal muscle morphogenesis are critical developmental processes that require ongoing coordination and signaling between cells and the matrix of their surrounding environment. The extracellular matrix (ECM) itself is a complex and dynamic structure whose regulation is of the utmost importance to cell behavior. While it is well characterized that the ECM is essential for organogenesis, it is less known how ECM composition informs development. Here, we show that the transmembrane protein Tmem2 is an essential regulator of ECM organization during cardiac and skeletal muscle morphogenesis. In zebrafish, maternal and zygotic depletion of tmem2 renders embryos unable to form primitive heart tubes, whereas in muscle tissue this same loss results in destabilization of muscle fibers. In contrast, zygotic loss of tmem2 results in ectopic atrioventricular canal (AVC) differentiation. All three of these striking phenotypes are accompanied by disorganized and defective ECM deposition, reflecting an important role for Tmem2 in regulation of the extracellular environments that impact development. The molecular mechanism of Tmem2 function, however, is unclear. Our results identify the structural requirements for Tmem2 activity across multiple developmental roles. Further, our studies characterize disorganization of the ECM in tmem2 mutants. Finally, our findings support the model that Tmem2 directly influences ECM structure and composition in a context-dependent manner, while maintaining the possibility that Tmem2 can have additional mechanisms of activity.