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Researchers identify role of gene in placental development

A recent study has shown that the gene GPR126 plays an essential role in the development of the placenta during pregnancy.

GPCRs

Adhesion G protein–coupled receptors (aGPCRs) are a large family of cell surface receptors. They are involved in a number of signalling events, which occur through their large extracellular domain (ECD). These receptors also contain a characteristic seven-transmembrane helix (7TM) domain and a short intracellular domain. The membrane-proximal portion of the ECD, adjacent to the 7TM, is a conserved GPCR autoproteolysis inducing (GAIN) domain.

GPR126 is a member of the aGPCR family and is encoded by the ADGRG6 gene. In mice and zebrafish, Gpr126 is encoded by 25 exons and exists in several alternatively spliced forms. The Gpr126 locus is also highly conserved in vertebrates, and the synteny of the genomic region surrounding these genes is conserved in fish, birds, reptiles and mammals. This indicates that the predicted genes are true orthologues. Gpr126 is important in multiple processes, including peripheral nervous system myelination, bone formation and inner ear development. Moreover, human GPR126 mutations are associated with skeletal malformations and muscle cramping in the limbs.

The role for Gpr126 in placentation

In a recent study, published in Science Advances, scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) used experimental mouse and zebrafish models to study the function of GPR126.

The team showed that global Gpr126 inactivation in mice caused thinning of the walls of the heart and resulted in embryonic death. However, endocardium-specific GPR126 deletion did not affect embryonic development and cardiac development or function. Furthermore, expression of GPR126 in the endocardium did not rescue lethality in GPR126-deficient mice. This suggests that embryonic demise is not due to defective cardiac development. Further experiments in zebrafish confirmed that GPR126 is not involved in heart development.

During embryonic development, GPR126 is expressed in trophoblast cells, a cell type specific to the placenta. The team demonstrated that inactivation of this gene in the embryo is compatible with life if the placenta retained at least one normal copy. However, inactivation of the gene in both the embryo and placenta caused embryonic death. The researchers showed that trophoblast GPR126 is key for the expression of specific proteases involved in vasculature remodelling. This process is critical for the viability of the foetus. Defects in this process are associated with pregnancy complications such as preeclampsia, restricted foetal growth and miscarriage.

Overall, this study highlights that heart abnormalities in Gpr126 mutants are secondary to placental defects. It is important that research into therapies aimed at modulating aGPCR signalling take into consideration the potential deleterious effects in pregnancy.

Image credit: canva


More on these topics

Genetic Variants / Heart / Placenta