Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice
- University of Cambridge, United Kingdom
- The Babraham Institute, United Kingdom
Abstract
Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110α in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110α differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110α in the different compartments of the conceptus, which control fetal resource acquisition and growth.
Data availability
The RNA-seq data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE126046 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126046). All other relevant data are within the manuscript and its Supporting Information files.
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Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetusNCBI Gene Expression Omnibus, GSE126046.
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A novel role of Tet1/2 proteins in cell cycle progression of trophoblast stem cellsNCBI Gene Expression Omnibus, GSE109545.
Article and author information
Author details
Amanda N Sferruzzi-Perri
Funding
Centre for Trophoblast Research (NGF)
- Amanda N Sferruzzi-Perri
Royal Society Dorothy Hodgkin
- Amanda N Sferruzzi-Perri
Royal Society Newton International
- Jorge López-Tello
COST EU ACTION (SALAAM)
- Jorge López-Tello
ERASMUS EU
- Jorge López-Tello
COST EU ACTION (EPICONCEPT)
- Jorge López-Tello
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Elizabeth Robertson, University of Oxford, United Kingdom
Ethics
Animal experimentation: All experiments were carried out in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Board. Home Office project license number is 70/7645.
Version history
- Received: January 18, 2019
- Accepted: June 25, 2019
- Accepted Manuscript published: June 26, 2019 (version 1)
- Version of Record published: July 16, 2019 (version 2)
Copyright
© 2019, López-Tello et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice
eLife 8:e45282.
https://doi.org/10.7554/eLife.45282
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