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Cited by 31Ion Channels and ReceptorsCardiac electrophysiology and arrhythmiasDevelopmental Biology and Gene Regulation

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

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Yang, Feili, Huang, Lei, Tso, Alexandria, Wang, Hong, Cui, Li, Lin, Lizhu, Wang, Xiaohong, Ren, Mingming +5 more·2020·PLOS Genetics
DOI 10.1371/journal.pgen.1008739PMC PMC7176088
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Abstract

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.

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Authors
Yang, F., Huang, L., Tso, A., Wang, H., Cui, L., Lin, L., Wang, X., Ren, M., Fang, X., Liu, J., Han, Z., Chen, J., & Ouyang, K.
Affiliations
  • Peking University (CN)
  • Peking University Shenzhen Hospital (CN)
  • University of California San Diego (US)
  • Tianjin Medical University (CN)
  • Shenzhen University (CN)
Corresponding author
  • Han, Zhen
  • Chen, Ju
  • Ouyang, Kunfu
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2020-04-22
Volume
16
Issue
4
Pages
e1008739
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1008739
PMC
PMC7176088
OpenAlex
W3017077727
Cited by
31
References
1
Citations by year
2026: 2 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 1
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (31370823, 81970421)
  • Science and Technology Planning Project of Shenzhen Municipality (JCYJ20160428154108239, KQJSCX20170330155020267)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
IP3 receptor, IP3R1, IP3R2, IP3R3, ITPR2, ITPR3, conditional knockout mice, embryonic lethality, cardiovascular defects, placental abnormalities, allantois, umbilical vessels, placental labyrinth, epiblast, embryonic development, calcium signaling
MeSH terms
Animals, Female, Fetal Growth Retardation, Fetal Heart, Heart Defects, Congenital, Male, Mice, Inbred C57BL, Placenta, Pregnancy, Gene Deletion, Myocytes, Cardiac, Mice, Inositol 1,4,5-Trisphosphate Receptors, Endothelial Progenitor Cells

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