Adgrg6/Gpr126 is required for compact wall integrity and establishing trabecular identity during cardiac...

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Cell Biology

Background:

• Adhesion G protein-coupled receptors (aGPCRs) play crucial roles in development, but their precise functions remain largely unknown.
• The aGPCR Gpr126 is implicated in heart trabeculation, a process vital for cardiac function.
• Defects in heart trabeculation can lead to cardiomyopathies and cardiac dysfunction.

Purpose of the Study:

• To elucidate the distinct roles of Gpr126 domains in regulating cardiomyocyte development and heart trabeculation.
• To understand how cardiomyocytes acquire trabecular identity during cardiac development.

Main Methods:

• Utilized maternal zygotic (MZ) gpr126^stl47 and gpr126^st49 mutants with specific domain deletions.
• Analyzed N-cadherin localization and cardiomyocyte polarization in mutant models.
• Investigated the impact of endocardial Gpr126 C-terminal fragment (CTF) expression on trabeculation.

Main Results:

• MZ gpr126^stl47 mutants displayed hypotrabeculation with random N-cadherin distribution in compact layer cardiomyocytes.
• Mutants expressing a Gpr126 N-terminal fragment lacking the GPS motif (NTF^ΔGPS) showed a multilayered ventricular wall with normal N-cadherin localization and increased Notch activity.
• Endocardial CTF expression rescued trabeculation defects in gpr126^st49 mutants.

Conclusions:

• Gpr126's N-terminal fragment (NTF) is essential for maintaining compact wall integrity and cell-cell adhesion.
• Gpr126's C-terminal fragment (CTF) is critical for establishing cardiomyocyte trabecular identity.
• Distinct domains of Gpr126 play specific, non-redundant roles in regulating heart development and trabeculation.