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


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: 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


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