What is the clinical evidence from this study?

Study design: Other. Population: Cardiac trabeculation defects. Intervention: Gpr126 mutations (stl47, st49) and domain-specific rescue (CTF, NTF) vs. Wild type (WT) siblings. Primary outcome: Cardiac trabeculation phenotype (hypotrabeculation or multilayered ventricular wall).

What does this research mean for the field?

Gpr126-CTF overexpression reinstated trabeculation in 90.9% of maternal zygotic gpr126st49 mutant hearts compared to normal trabeculation in wild type. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to clarify how Gpr126 influences heart development, specifically trabeculation.

February 10, 20260 citations

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

SSSwati SrivastavaGoethe University Frankfurt FGFelix GunawanUniversity of Toronto SVSilvia VergarajaureguiNational Institutes of Health

Key Result

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.

Key Points

This research aims to clarify how Gpr126 influences heart development, specifically trabeculation.
Examined maternal zygotic gpr126 truncation mutants to assess trabeculation effects.
Analyzed N-cadherin localization and Notch activity in various gpr126 mutant lines.
Utilized endocardially expressed gpr126 C-terminal fragments to evaluate trabeculation restoration.
gpr126stl47 mutants displayed significant hypotrabeculation with disorganized N-cadherin distribution.
gpr126st49 mutants exhibited a multilayered ventricular wall with normal N-cadherin localization and enhanced Notch activity.
Restoration of trabeculation was achieved with gpr126 C-terminal fragments in specific mutant models.

Structured PICO

Population

Zebrafish embryos (wild type, gpr126stl47, and gpr126st49 mutants) and human retinal pigment epithelial cell line ARPE-19

Intervention

Genetic mutation and ectopic expression of Gpr126 N-terminal fragment (NTF) and C-terminal fragment (CTF)

Comparator

Wild type (WT) zebrafish and WT-transfected cells

Outcome

Cardiac trabeculation phenotypes (hypotrabeculation, multilayered ventricular wall, normal trabeculation) at 96 and 120 hours post fertilization

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.

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.

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