Glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis
Posted on: 28 November 2019
Preprint posted on 31 October 2019
Article now published in Developmental Cell at http://dx.doi.org/10.1016/j.devcel.2020.02.015
It’s a sweet story: Glucose metabolism regulates YAP localization and AP-2gamma translation to control the first cell fate decision in development
Selected by Grace Lim
Categories: cell biology, developmental biology
Background
Mammalian preimplantation development is the process of converting a fertilized zygote into an implantation-ready blastocyst. Over a span of 3 to 4 days in the mouse, the embryo undergoes a series of cleavage divisions, inner-outer cell positioning, and cavity expansion to produce a blastocyst with two distinct and well-specified lineages – an outer trophectoderm (TE) layer and an inner cell mass (ICM). Common pathways known to be involved in TE-ICM fate specification of the preimplantation embryo include Hippo and Notch signalling, which can differentially regulate TE- and ICM-specific transcription factors in outer and inner cells, respectively1.
This study addresses another important but often under-appreciated aspect of development – the role of nutrition and metabolism in driving embryogenesis and cell fate specification. Historically, research interest in optimizing culture medium components to overcome the “2-cell block” (where cultured embryos become arrested at the 2-cell stage of development) was high, in order to establish embryo culture ex utero. Although these culture conditions are now well-established, the precise roles of each metabolite remain vaguely explored. Here, the authors discover an exciting new role for glucose in regulating TE specification in the preimplantation embryo, via YAP localization and AP-2gamma translation.
Key findings
In agreement with previous work, the authors first demonstrate the unique requirement for glucose in ensuring proper morula to blastocyst development. Embryos grown in the absence of glucose arrest precisely at the compacted 8-cell stage of development, and subsequently undergo fragmentation.
Surprisingly, although glucose uptake is high during the morula to blastocyst transition, the authors find that glucose is not required for energy production (via glycolysis and the TCA cycle), nor utilized in amino acid, fatty acid or nucleobase synthesis. Instead, glucose plays key roles in two other metabolic pathways: the hexosamine biosynthetic pathway (HBP) and the pentose phosphate pathway (PPP). Using a combination of drug inhibitors, targeted removal of pathway components, and rescue experiments, they demonstrate that HBP and PPP are necessary drivers of the morula to blastocyst transition.
The authors go on to investigate a novel role for glucose metabolism in TE-ICM fate specification, which occurs precisely during the morula to blastocyst transition. Blocking HBP, PPP, or removing glucose reduces expression of the TE-specific transcription factor Cdx2, while levels of the ICM-specific Oct4 and Nanog remain unchanged, suggesting that glucose regulates TE but not ICM specification.
Further investigation into TE-specification regulators revealed that glucose metabolism acts along two pathways: 1) together with lipid signalling, translation of AP-2gamma via PPP, and 2) O-linked glycosylation of YAP resulting in nuclear YAP localization via HBP. In combination, YAP1 and AP-2gamma assemble as part of a larger transcriptional complex to drive the expression of Cdx2, specifying the outer trophectoderm fate in the embryo.
What I like about this preprint
While the idea of a link between metabolism and fate specification has been toyed with in earlier publications2,3, this preprint is one of the first to demonstrate a clear relationship between glucose and TE fate specification in the preimplantation mouse embryo. The authors do a great job at teasing apart the individual pathways involved in glucose metabolism, and integrating past studies with the new findings to provide a unified picture of the role of glucose in these early stages of development and fate specification. With this work, there could be renewed interest in the developmental biology field for what the authors call “Developmental Metabolism”.
From a technical standpoint, this paper also sets new standards for embryo manipulation techniques. The authors address technical limitations of individual techniques (such as the potential off-target effects of drug inhibitors) by drawing conclusions across multiple manipulation experiments. Notably, the authors demonstrate in the embryo the usage of the recently established Trim-Away method, which inhibits protein function by directly targeting its removal at the protein level. This has clear advantages over traditional strategies that target transcripts purely at the RNA level. In the context of the mouse embryo, Trim-Away could be a particularly useful tool targeting proteins present during the early stages of embryonic development, when maternal products can still be retained and function within the embryo.
Future directions and questions for the authors
- The authors show that glucose metabolism has a specific role in controlling Cdx2 expression in the outer cells of the embryo, while such a role appears to be irrelevant for inner cells. This was inferred from the unchanged levels of ICM-specific markers Oct4 and Nanog upon perturbation of HBP and PPP pathways. However, given that Cdx2 and Oct4/Nanog have well-established reciprocal relationships4,5, can the authors suggest why there was no corresponding rise in Oct4/Nanog along with the diminished Cdx2 levels in those manipulated embryos?
- It may be interesting to consider how outer and inner cells could uptake and/or metabolise glucose differently, contributing to differential cell fate specification outcomes. Do outer and inner cells express varying levels of glucose transporters, and do the outer and inner cell micro-environments contribute to distinct patterns of glucose uptake and/or metabolism?
- How does the glucose metabolism pathway feed into and interact with known modes of cell fate specification? For instance, both glucose metabolism and Hippo signalling regulate the control of YAP localization to drive TE-specific Cdx2 expression. Did the authors consider any cross-talk between the two pathways that would drive proper YAP localization within the embryo?
References
- Chazaud, C. & Yamanaka, Y. Lineage specification in the mouse preimplantation embryo. Development 143, 1063–1074 (2016).
- Mandal, S. et al. Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 29(3), 486–495 (2011).
- Folmes, C.D.L. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metabolism 14, 264–271 (2011).
- Huang, D. et al. The role of Cdx2 as a lineage specific transcriptional repressor for pluripotent network during the first developmental cell lineage segregation. Scientific Reports 7, 17156 (2017).
- Niwa H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 91 –929 (2005).
doi: https://doi.org/10.1242/prelights.15412
Read preprint
(No Ratings Yet)Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Motor Clustering Enhances Kinesin-driven Vesicle Transport
Sharvari Pitke
Cellular signalling protrusions enable dynamic distant contacts in spinal cord neurogenesis
Ankita Walvekar
Green synthesized silver nanoparticles from Moringa: Potential for preventative treatment of SARS-CoV-2 contaminated water
Safieh Shah, Benjamin Dominik Maier
Also in the developmental biology category:
Cellular signalling protrusions enable dynamic distant contacts in spinal cord neurogenesis
Ankita Walvekar
Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation
Ryan Harrison
HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos
Anchel De Jaime Soguero
preLists in the cell biology category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the developmental biology category:
BSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
| List by | Joyce Yu, Katherine Brown |
GfE/ DSDB meeting 2024
This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.
| List by | Joyce Yu |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
| List by | Nándor Lipták |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
| List by | Jesus Victorino |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
| List by | Alex Eve |
Society for Developmental Biology 79th Annual Meeting
Preprints at SDB 2020
| List by | Irepan Salvador-Martinez, Martin Estermann |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EDBC Alicante 2019
Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.
| List by | Sergio Menchero et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
| List by | Alex Eve |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
| List by | Alex Eve |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
| List by | Alexa Sadier |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
| List by | Shikha Nayar |