Delineating the role of CTF and NTF of Gpr126 in physiology and pathophysiology

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The major activation mechanism of adhesion G protein-coupledreceptor (aGPCRs) signaling is the interaction of a cryptic tetheredagonist with the seven transmembrane domain. This agonist can beliberated by autocatalytical cleavage at the GPS motif within the GAINdomain, yielding an N-terminal fragment (NTF) and a C-terminalfragment (CTF) or through isomerization upon changes occurring atthe NTF such as ligand binding or mechanical force. The aGPCRGpr126 (Adgrg6) is essential for heart, ear, and Schwann celldevelopment. However, while Gpr126 knockout (KO) mice exhibit aheart and peripheral nerve phenotype, zebrafish mutants lacking theCTF exhibit only the peripheral nerve phenotype, suggesting that theNTF has a specific role in heart. Moreover, rescue experiments inzebrafish suggest that GPR126 has domain-specific functions. Yet,such a phenomenon has not been described for any other aGPCR, nodata in mouse are available, and it remains unclear whether receptorcleavage is important as well as which functions the individualdomains have. To demonstrate that the NTF has an independentfunction from the CTF, we have obtained or generated during the firstfunding period several animal models including Gpr126 reporter mice,conditional Gpr126 KO mice and several transgenic zebrafish lines.Analysis of these models identified several gross morphological aswell as cellular and molecular phenotypes upon alteration of Gpr126expression. During the second funding period we will continue thestructure-function analysis of Gpr126. An important focus of our workis to determine if the embryonic lethal phenotype in Gpr126 KO miceis indeed due to defective heart development and whether NTFexpression in endocardial cells is sufficient for proper heartdevelopment. Further, we will elucidate the role of Gpr126 in heartvalve development as our data suggest a role for Gpr126 inendothelial mesenchymal transformation. Finally, we will characterizethe role of Gpr126 during kidney physiology and pathophysiology. Ourdata indicate that Gpr126 is expressed in several renal cell types.Moreover, its expression is highly upregulated upon injury. Finally, ourdata suggest that the NTF might act in the heart as well as in thekidney in a paracrine manner. Collectively, we have generated a widevariety of tools that will allow us to delineate the role of CTF and NTFof Gpr126 in physiology and pathophysiology contributing to a betterunderstanding of aGPCR signaling and function.