Organ-specific function of adhesion G protein-coupled receptor Gpr126 is domain dependent

Despite their abundance and multiple functions in a variety of organ systems, the function andsignaling mechanisms of adhesion G protein coupled receptors (aGPCRs) are poorly understood. Adhesion-GPCRs possess large N-termini (NTF) containing various functional domains, which can be autoproteolytically cleaved at their GPS site from their C-termini (CTF). Here, we demonstrate that Gpr126 is expressed in the endocardium during early mouse heart development. Gpr126 knockout in mice and knockdown in zebrafish causes hypotrabeculation and affects mitochondrial function. Ectopic expression of the NTF part of Gpr126 in zebrafish rescued the cardiac trabeculation but not the previously described myelination phenotype in peripheral neurons. These data demonstrate that Gpr126-NTF in contrast to Gpr126-CTF plays an important role in heart development. Collectively, our analysis provides a new example of the versatile function and signaling properties of adhesion-GPCRs in vertebrates.