Key result
In zebrafish, Gpr126 N-terminal fragment maintains compact wall integrity while C-terminal fragment establishes trabecular identity.
Why the study?
How adhesion G protein-coupled receptors control development and how cardiomyocytes attain trabecular identity during heart trabeculation remain poorly understood.
Gpr126 has domain-specific roles during cardiac trabeculation, with the N-terminal fragment maintaining compact wall integrity and the C-terminal fragment providing trabecular identity.
Zebrafish Gpr126 fragment roles should not yet alter clinical practice; leaves open their relevance to mammalian trabeculation defects.
How adhesion G protein-coupled receptors (aGPCRs) control development remains unclear. aGPCR Adgrg6/Gpr126 has been associated with heart trabeculation. Defects in this process cause cardiomyopathies and cardiac dysfunction. How cardiomyocytes attain trabecular identity is poorly understood. Here, we show that different domains of Gpr126 distinctly regulate compact wall integrity and trabecular identity. Maternal zygotic (MZ) gpr126stl47 early truncation mutants exhibit hypotrabeculation, whereby N-cadherin distributes randomly along apical/basal/lateral membranes of compact layer cardiomyocytes. In contrast, zygotic and MZ gpr126st49 mutants, expressing a N-terminal fragment lacking the GPS motif (NTFΔGPS), exhibit a multilayered ventricular wall containing polarized cardiomyocytes with normal N-cadherin localization and increased Notch activity. Notably, endocardially expressed gpr126 C-terminal fragment (CTF) reinstates trabeculation in gpr126st49 mutants. Collectively, our data reveal domain-specific roles of Gpr126 during trabeculation, whereby the NTF is required for maintaining cell-cell adhesion and compact wall integrity, whereas the CTF is essential to provide trabecular identity.
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Srivastava et al. (2026) studied Cardiac trabeculation defects. Gpr126 mutations (stl47, st49) and domain-specific rescue (CTF, NTF) vs. Wild type (WT) siblings was evaluated on Cardiac trabeculation phenotype (hypotrabeculation or multilayered ventricular wall). In zebrafish models, the Gpr126 N-terminal fragment maintains compact wall integrity, whereas the C-terminal fragment is essential for establishing trabecular identity during cardiac trabeculation.
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