Inositol 1,4,5-trisphosphate receptors are essential for fetal-maternal connection and embryo viability

English version

Autoři: Feili Yang ^aff001; Lei Huang ^aff002; Alexandria Tso ^aff003; Hong Wang ^aff001; Li Cui ^aff003; Lizhu Lin ^aff003; Xiaohong Wang ^aff004; Mingming Ren ^aff002; Xi Fang ^aff003; Jie Liu ^aff005; Zhen Han ^aff002; Ju Chen ^aff003; Kunfu Ouyang ^aff001
Působiště autorů: School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen, China ^aff001; Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, China ^aff002; University of California San Diego, School of Medicine, Department of Medicine, La Jolla, CA, United States of America ^aff003; Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China ^aff004; Department of Pathophysiology, School of Medicine, Shenzhen University, Shenzhen, China ^aff005
Vyšlo v časopise: Inositol 1,4,5-trisphosphate receptors are essential for fetal-maternal connection and embryo viability. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008739
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008739

Souhrn

Inositol 1,4,5‐trisphosphate receptors (IP₃Rs) are a family of intracellular Ca²⁺ release channels located on the ER membrane, which in mammals consist of 3 different subtypes (IP₃R1, IP₃R2, and IP₃R3) encoded by 3 genes, Itpr1, Itpr2, and Itpr3, respectively. Studies utilizing genetic knockout mouse models have demonstrated that IP₃Rs are essential for embryonic survival in a redundant manner. Deletion of both IP₃R1 and IP₃R2 has been shown to cause cardiovascular defects and embryonic lethality. However, it remains unknown which cell types account for the cardiovascular defects in IP₃R1 and IP₃R2 double knockout (DKO) mice. In this study, we generated conditional IP₃R1 and IP₃R2 knockout mouse models with both genes deleted in specific cardiovascular cell lineages. Our results revealed that deletion of IP₃R1 and IP₃R2 in cardiomyocytes by TnT-Cre, in endothelial / hematopoietic cells by Tie2-Cre and Flk1-Cre, or in early precursors of the cardiovascular lineages by Mesp1-Cre, resulted in no phenotypes. This demonstrated that deletion of both IP₃R genes in cardiovascular cell lineages cannot account for the cardiovascular defects and embryonic lethality observed in DKO mice. We then revisited and performed more detailed phenotypic analysis in DKO embryos, and found that DKO embryos developed cardiovascular defects including reduced size of aortas, enlarged cardiac chambers, as well as growth retardation at embryonic day (E) 9.5, but in varied degrees of severity. Interestingly, we also observed allantoic-placental defects including reduced sizes of umbilical vessels and reduced depth of placental labyrinth in DKO embryos, which could occur independently from other phenotypes in DKO embryos even without obvious growth retardation. Furthermore, deletion of both IP₃R1 and IP₃R2 by the epiblast-specific Meox2-Cre, which targets all the fetal tissues and extraembryonic mesoderm but not extraembryonic trophoblast cells, also resulted in embryonic lethality and similar allantoic-placental defects. Taken together, our results demonstrated that IP₃R1 and IP₃R2 play an essential and redundant role in maintaining the integrity of fetal-maternal connection and embryonic viability.

Klíčová slova:

Embryos – Growth restriction – Mesoderm – Mouse models – placenta – Trophoblasts – Umbilical cord – Somites

Zdroje

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