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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jorge López-Tello

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Vicente Pérez-García

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jaspreet Khaira

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Laura C Kusinski

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Wendy N Cooper

    Metabolic Research Laboratories, MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3416-9982
  6. Adam Andreani

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Imogen Grant

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Edurne Fernández de Liger

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Brian YH Lam

    Metabolic Research Laboratories and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Myriam Hemberger

    Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Ionel Sandovici

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5674-4269
  12. Miguel Constancia

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Amanda N Sferruzzi-Perri

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    ans48@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4931-4233

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.

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.

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.

Metrics

  • 2,395
    views
  • 313
    downloads
  • 31
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jorge López-Tello
  2. Vicente Pérez-García
  3. Jaspreet Khaira
  4. Laura C Kusinski
  5. Wendy N Cooper
  6. Adam Andreani
  7. Imogen Grant
  8. Edurne Fernández de Liger
  9. Brian YH Lam
  10. Myriam Hemberger
  11. Ionel Sandovici
  12. Miguel Constancia
  13. Amanda N Sferruzzi-Perri
(2019)
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

Share this article

https://doi.org/10.7554/eLife.45282

Further reading

    1. Computational and Systems Biology
    2. Developmental Biology
    Rosalio Reyes, Arthur D Lander, Marcos Nahmad
    Research Article

    Understanding the principles underlying the design of robust, yet flexible patterning systems is a key problem in developmental biology. In the Drosophila wing, Hedgehog (Hh) signaling determines patterning outputs using dynamical properties of the Hh gradient. In particular, the pattern of collier (col) is established by the steady-state Hh gradient, whereas the pattern of decapentaplegic (dpp), is established by a transient gradient of Hh known as the Hh overshoot. Here we use mathematical modeling to suggest that this dynamical interpretation of the Hh gradient results in specific robustness and precision properties. For instance, the location of the anterior border of col, which is subject to self-enhanced ligand degradation is more robustly specified than that of dpp to changes in morphogen dosage, and we provide experimental evidence of this prediction. However, the anterior border of dpp expression pattern, which is established by the overshoot gradient is much more precise to what would be expected by the steady-state gradient. Therefore, the dynamical interpretation of Hh signaling offers tradeoffs between

    1. Developmental Biology
    Sebastian Deichsel, Lisa Frankenreiter ... Anja C Nagel
    Research Article

    Notch signalling activity regulates hematopoiesis in Drosophila and vertebrates alike. Parasitoid wasp infestation of Drosophila larvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here, we show that the Drosophila CSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation. As this phosphorylation interferes with the DNA binding of Su(H), it reversibly precludes its activity. Accordingly, phospho-deficient Su(H)S269A mutants are immune-compromised. A screen for kinases involved in Su(H) phosphorylation identified Pkc53E, required for normal hematopoiesis as well as for parasitoid immune response. Genetic and molecular interactions support the specificity of the Su(H)-Pkc53E relationship. Moreover, phorbol ester treatment inhibits Su(H) activity in vivo and in human cell culture. We conclude that Pkc53E targets Su(H) during parasitic wasp infestation, thereby remodelling the blood cell population required for wasp egg encapsulation.