GLUT3 gene expression is critical for embryonic growth, brain development and survival

Carayannopoulos, Mary O.; Xiong, Fuxia; Jensen, Penny; Rios-Galdamez, Yesenia; Huang, Haigen; Lin, Shuo; Devaskar, Sherin U.

doi:10.1016/j.ymgme.2014.01.013

Cited by 15 publications

(13 citation statements)

References 25 publications

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“…This effect on pluripotency is more severe as the expression of GLUT3, and presumably the rate of glucose consumption, is reduced further. This is consistent with the previously measured dose-dependent effect on early development, including aberrant brain organogenesis, measured when a morpholino was used to silence the GLUT3 orthologue in zebrafish 45 .…”

Section: Discussionsupporting

confidence: 91%

GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells

Christensen

Calder

Houghton

2015

Sci Rep

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Human embryonic stem cells (hESCs) have the capacity to differentiate into all cell types and thus have great potential for regenerative medicine. hESCs cultured at low oxygen tensions are more pluripotent and display an increased glycolytic rate but how this is regulated is unknown. This study therefore aimed to investigate the regulation of glucose metabolism in hESCs and whether this might impact OCT4 expression. In contrast to the glucose transporter GLUT1, GLUT3 was regulated by environmental oxygen and localised to hESC membranes. Silencing GLUT3 caused a reduction in glucose uptake and lactate production as well as OCT4 expression. GLUT3 and OCT4 expression were correlated suggesting that hESC self-renewal is regulated by the rate of glucose uptake. Surprisingly, PKM2, a rate limiting enzyme of glycolysis displayed a nuclear localisation in hESCs and silencing PKM2 did not alter glucose metabolism suggesting a role other than as a glycolytic enzyme. PKM2 expression was increased in hESCs cultured at 5% oxygen compared to 20% oxygen and silencing PKM2 reduced OCT4 expression highlighting a transcriptional role for PKM2 in hESCs. Together, these data demonstrate two separate mechanisms by which genes regulating glucose uptake and metabolism are involved in the hypoxic support of pluripotency in hESCs.

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Section: Discussionsupporting

confidence: 91%

GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells

Christensen

Calder

Houghton

2015

Sci Rep

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“…Functional studies implicated altered expression of the glucose transporter encoded by SLC2A3 (GLUT3) as a cause of cardiovascular, neuronal, and immunological abnormalities in affected CNV carriers. SLC2A3 is expressed in the brain, pharyngeal arches, and left ventricular outflow tract during development, and knockdown of the mouse and zebrafish orthologs causes early embryonic lethality [Ganguly et al, ; Carayannopoulos et al, ]. Mutation of SLC2A10 , a paralog of SLC2A3 , causes arterial tortuosity syndrome, a developmental disorder characterized by congenital malformations, aneurysms, and dissections of the aorta and other arteries [Cheng et al, ].…”

Section: Discussionmentioning

confidence: 99%

Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry

Prakash

Bondy

Maslen

et al. 2016

American J of Med Genetics Pt A

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Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14 and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS.

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“…Heterozygous knockout of GLUT3 in mice leads to abnormal brain development and some behavioural abnormalities that resemble those of autistic spectrum disorders. These GLUT3 partial knockout phenotypes indicate an important role in many aspects of neuronal function [34,182,233].…”

Section: Glut2mentioning

confidence: 98%

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Holman

2020

Pflugers Arch - Eur J Physiol

142

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The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long-and shorttime scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins.

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GLUT3 gene expression is critical for embryonic growth, brain development and survival

Cited by 15 publications

References 25 publications

GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells

GLUT3 and PKM2 regulate OCT4 expression and support the hypoxic culture of human embryonic stem cells

Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

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