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Transcriptomic effects of GLUT2 knock-down in zebrafish embryos

ABSTRACT: Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency.

ORGANISM(S): Danio rerio

PROVIDER: GSE57836 | GEO | 2014/12/23

SECONDARY ACCESSION(S): PRJNA248211

REPOSITORIES: GEO

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Transcriptomic effects of GLUT2 knock-down in zebrafish embryos

Project description:Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency. Control and ATG morphant embryos were harvested at 72 hpf and RNA samples were obtained from pools of 20 embryos per condition and three pooled biological replicates of control and ATG morphants were analyzed.

2014-12-23 | E-GEOD-57836 | biostudies-arrayexpress

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Project description:Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C > T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

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Hepatic glucose sensing is required to preserve beta-cell glucose competence

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Hepatic glucose sensing is required to preserve beta-cell glucose competence

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