Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/11576
Adhesion G protein-coupled receptor Gpr126 signaling is essential for placental development
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Gpr126 is an adhesion G protein-coupled receptor (GPCR) that is required for peripheral nervous system (PNS) development in mice and zebrafish. In the heart, Gpr126 is expressed in the endocardium and its inactivation in mice leads to embryonic lethality and defective ventricular trabeculation. These defects are also recapitulated in zebrafish larvae using morpholinos, but the mechanistic bases of this phenotype are unknown. Here, we have generated a series of standard, conditional loss- and gain-of-function alleles in mice and zebrafish, to decipher the role of Gpr126 in development. We found that Gpr126 standard knockout mice lacking exons 3 and 4 (Gpr126Δ3,4) develop to term and show abnormal joint stiffness in the forelimbs and hindlimbs and impaired mobility, indicating that the deleted CUB and PTX adhesive domains are essential for PNS development. Deletion of exon 7 disrupts Gpr126 protein translation, and Gpr126Δ7 mice show a thinner ventricular wall and trabeculae and die at embryonic day 13.5 (E13.5) with no signs of ventricular patterning, metabolic or proliferation defects. In contrast, endocardial-specific deletion of exon 7 in Gpr126flox mice does not cause lethality, and mutant mice are normal and reach adulthood. In addition, gpr126 nonsense and promoter-less zebrafish mutants show normal trabeculation. Interestingly, the embryonic lethality of Gpr126Δ7 mice is not rescued by transgenic expression of GPR126 in the endocardium, suggesting that the cause of death is likely due to defective development of another tissue. Gpr126 is also expressed in the trophoblast giant cells that invade and remodel the maternal spiral arteries of the placenta. Gpr126Δ7 mutant placentas show downregulation of two placenta-specific cathepsins, Cts7 and Cts8, the last one involved in the maternal uterine vasculature remodeling from high-resistant to low-resistant vessels, by mediating the loss of smooth muscle α-actin. These changes in vessel architecture allow a crucial increase in the blood flow supply to the fetus at much-reduced pressure, and failure of this process can lead to pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and preeclampsia. We have used the Sox2-Cre driver line, active in the maternal germline or the zygote depending on its female or male origin, to establish the requirement of Gpr126 for placentation and embryonic development. We found that Gpr126Δ7 homozygous mutants associated with a heterozygous placenta survive to term but show typical Gpr126-defective PNS phenotypes. In contrast, homozygous mutants associated with a mutant placenta die at the same stages that Gpr126Δ7 mutants. In summary, we demonstrated that Gpr126 is essential in the trophoblast-derived cell lineage to sustain embryonic progression, by promoting spiral artery remodeling during placental development. We propose the placenta-heart axis as an explanation for heart abnormalities concurrent with placental defects in Gpr126 mouse mutants.
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