Inositol 1,4,5-trisphosphate receptors are essential for fetal-maternal connection and embryo viability.
Animals
Endothelial Progenitor Cells
/ metabolism
Female
Fetal Growth Retardation
/ genetics
Fetal Heart
/ embryology
Gene Deletion
Heart Defects, Congenital
/ genetics
Inositol 1,4,5-Trisphosphate Receptors
/ genetics
Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
/ metabolism
Placenta
/ embryology
Pregnancy
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
14
01
2020
accepted:
25
03
2020
entrez:
23
4
2020
pubmed:
23
4
2020
medline:
4
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32320395
doi: 10.1371/journal.pgen.1008739
pii: PGENETICS-D-20-00053
pmc: PMC7176088
doi:
Substances chimiques
Inositol 1,4,5-Trisphosphate Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008739Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL143210
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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