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Glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis

Fangtao Chi, Mark S. Sharpley, Raghavendra Nagaraj, Shubhendu Sen Roy, Utpal Banerjee

Preprint posted on October 31, 2019 https://www.biorxiv.org/content/10.1101/826875v1

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

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.

 

Fig. 1A from Chi et al.: Embryos grown in the absence of glucose become arrested at the compacted morula stage, and do not successfully form a blastocyst. Made available under a CC-BY-NC-ND 4.0 International license.

 

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.

 

Fig. 5A-F from Chi et al.: Two regulators of Cdx2 expression, YAP1 and AP-2gamma, are found to be significantly reduced in the absence of glucose. Made available under a CC-BY-NC-ND 4.0 International license.

 

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

  1. Chazaud, C. & Yamanaka, Y. Lineage specification in the mouse preimplantation embryo. Development 143, 1063–1074 (2016).
  2. Mandal, S. et al. Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells 29(3), 486–495 (2011).
  3. Folmes, C.D.L. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metabolism 14, 264–271 (2011).
  4. 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).
  5. Niwa H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 91 –929 (2005).

 

Posted on: 28th November 2019

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