Lactate production by the mammalian blastocyst: Manipulating the microenvironment for uterine implantation and invasion?

Gardner, David K.

doi:10.1002/bies.201400155

Cited by 120 publications

(108 citation statements)

References 100 publications

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“…In tumors or in blastocysts embryos, cell motility is promoted by aerobic glycolysis which leads to acidification of the extracellular environment as a result of lactic acid excretion (Gardner, 2015; Parks et al, 2013). This in turn triggers activation of matrix metalloproteinases (MMP) involved in remodelling extracellular matrix.…”

Section: Resultsmentioning

confidence: 99%

A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos

Oginuma¹,

et al. 2017

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SUMMARY Mammalian embryos transiently exhibit aerobic glycolysis (Warburg effect), a metabolic adaptation also observed in cancer cells. The role of this particular type of metabolism during vertebrate organogenesis is currently unknown. Here, we provide evidence for spatiotemporal regulation of glycolysis in the posterior region of mouse and chicken embryos. We show that a posterior glycolytic gradient is established in response to graded transcription of glycolytic enzymes downstream of FGF signaling. We demonstrate that glycolysis controls posterior elongation of the embryonic axis by regulating cell motility in the presomitic mesoderm and by controlling specification of the paraxial mesoderm fate in the tail bud. Our results suggest that glycolysis in the tail bud coordinates Wnt and FGF signaling to promote elongation of the embryonic axis.

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Section: Resultsmentioning

confidence: 99%

A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos

Oginuma¹,

et al. 2017

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“…In pigs, both PKM2, the fetal form of pyruvate kinase that, when phosphorylated, has a much reduced pyruvate production, and HK2, a gene catalyzing the first step of glycolysis, are both up regulated in early embryos (Redel et al 2012). Considerable lactate is produced even by single embryos (Gott et al 1990;Sturmey and Leese 2003): indeed, lactate might have been co-opted for uterine invasion and implantation after blastocyst hatching (Gardner 2015) or it might balance the redox state of the cytosol (Dumollard et al 2009). …”

Section: Sources Of the Warburg Effect In Early Embryosmentioning

confidence: 96%

Some assembly required: evolutionary and systems perspectives on the mammalian reproductive system

2015

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In this review, we discuss the way that insights from evolutionary theory and systems biology shed light on form and function in mammalian reproductive systems. In the first part of the review, we contrast the rapid evolution seen in some reproductive genes with the generally conservative nature of development. We discuss directional selection and coevolution as potential drivers of rapid evolution in sperm and egg proteins. Such rapid change is very different from the highly conservative nature of later embryo development. However, it is not unique, as some regions of the sex chromosomes also show elevated rates of evolutionary change. To explain these contradictory trends, we argue that it is not reproductive functions per se that induce rapid evolution. Rather, it is the fact that biotic interactions, such as speciation events and sexual conflict, have no evolutionary endpoint and hence can drive continuous evolutionary changes. Returning to the question of sex chromosome evolution, we discuss the way that recent advances in evolutionary genomics and systems biology and, in particular, the development of a theory of gene balance provide a better understanding of the evolutionary patterns seen on these chromosomes. We end the review with a discussion of a surprising and incompletely understood phenomenon observed in early embryos: namely the Warburg effect, whereby glucose is fermented to lactate and alanine rather than respired to carbon dioxide. We argue that evolutionary insights, from both yeasts and tumor cells, help to explain the Warburg effect, and that new metabolic modeling approaches are useful in assessing the potential sources of the effect.

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“…Gardner (1998aGardner ( , 1998b identified the similarities between cancers and blastocysts, and the significance of the Warburg effect for the late stage embryo. More recently these concepts have been revisited (Krisher and Prather 2012;Redel et al 2012;Smith and Sturmey 2013;Gardner 2015), creating new insights and hypotheses on the roles of aerobic glycolysis in the mammalian blastocyst, and the potential significance of lactate as a signalling molecule.…”

Section: Introductionmentioning

confidence: 99%

Blastocyst metabolism

Gardner¹,

Harvey²

2015

Reprod. Fertil. Dev.

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123

108

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The mammalian blastocyst exhibits an idiosyncratic metabolism, reflecting its unique physiology and its ability to undergo implantation. Glucose is the primary nutrient of the blastocyst, and is metabolised both oxidatively and through aerobic glycolysis. The production of significant quantities of lactate by the blastocyst reflects specific metabolic requirements and mitochondrial regulation; it is further proposed that lactate production serves to facilitate several key functions during implantation, including biosynthesis, endometrial tissue breakdown, the promotion of new blood vessel formation and induction of local immune-modulation of the uterine environment. Nutrient availability, oxygen concentration and the redox state of the blastocyst tightly regulate the relative activities of specific metabolic pathways. Notably, a loss of metabolic normality is associated with a reduction in implantation potential and subsequent fetal development. Even a transient metabolic stress at the blastocyst stage culminates in low fetal weights after transfer. Further, it is evident that there are differences between male and female embryos, with female embryos being characterised by higher glucose consumption and differences in their amino acid turnover, reflecting the presence of two active X-chromosomes before implantation, which results in differences in the proteomes between the sexes. In addition to the role of Hypoxia-Inducible Factors, the signalling pathways involved in regulating blastocyst metabolism are currently under intense analysis, with the roles of sirtuins, mTOR, AMP-activated protein kinase and specific amino acids being scrutinised. It is evident that blastocyst metabolism regulates more than the production of ATP; rather, it is apparent that metabolites and cofactors are important regulators of the epigenome, putting metabolism at centre stage when considering the interactions of the blastocyst with its environment.

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Lactate production by the mammalian blastocyst: Manipulating the microenvironment for uterine implantation and invasion?

Cited by 120 publications

References 100 publications

A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos

A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos

Some assembly required: evolutionary and systems perspectives on the mammalian reproductive system

Blastocyst metabolism

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