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

## TL;DR

This study shows how the Gpr126 protein helps heart muscle cells form proper structures during heart development.

## Contribution

The study identifies distinct roles for different parts of Gpr126 in heart development.

## Key findings

- The N-terminal fragment of Gpr126 is needed for cell adhesion and compact wall integrity.
- The C-terminal fragment of Gpr126 is essential for establishing trabecular identity.
- Mutant forms of Gpr126 lead to defects in heart structure and function.

## Abstract

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.

Here they show that the adhesion GPCR Gpr126/Adgrg6 regulates trabeculation during heart development. Its N-terminal fragment is required for maintaining cell adhesion and compact wall integrity while its C-terminal fragment is essential to provide trabecular identity.