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GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling.

Human molecular genetics | Mar 15, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22116938

Growth factor signaling results in dramatic phenotypic changes in cells, which require commensurate alterations in cellular metabolism. Mutations in SLC2A10/GLUT10, a member of the facilitative glucose transporter family, are associated with altered transforming growth factor-β (TGFβ) signaling in patients with arterial tortuosity syndrome (ATS). The objective of this work was to test whether SLC2A10/GLUT10 can serve as a link between TGFβ-related transcriptional regulation and metabolism during development. In zebrafish embryos, knockdown of slc2a10 using antisense morpholino oligonucleotide injection caused a wavy notochord and cardiovascular abnormalities with a reduced heart rate and blood flow, which was coupled with an incomplete and irregular vascular patterning. This was phenocopied by treatment with a small-molecule inhibitor of TGFβ receptor (tgfbr1/alk5). Array hybridization showed that the changes at the transcriptome level caused by the two treatments were highly correlated, revealing that a reduced tgfbr1 signaling is a key feature of ATS in early zebrafish development. Interestingly, a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function. Consistent with these results, slc2a10 morphants showed decreased respiration and reduced TGFβ reporter gene activity. Finally, co-injection of antisense morpholinos targeting slc2a10 and smad7 (a TGFβ inhibitor) resulted in a partial rescue of smad7 morphant phenotypes, suggesting scl2a10/glut10 functions downstream of smads. Taken together, glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFβ signaling.

Pubmed ID: 22116938 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Cardiovascular Abnormalities | Glucose Transport Proteins, Facilitative | Luciferases | Mitochondria | Molecular Sequence Data | Morpholinos | Mutation | Notochord | Phenotype | Receptors, Transforming Growth Factor beta | Sequence Homology, Amino Acid | Signal Transduction | Transcriptome | Transforming Growth Factor beta | Zebrafish

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Associated grants

  • Agency: NHLBI NIH HHS, Id: HL084922
  • Agency: NHLBI NIH HHS, Id: HL090648
  • Agency: NCI NIH HHS, Id: P30 CA91842
  • Agency: NHLBI NIH HHS, Id: R01 HL090648
  • Agency: NCRR NIH HHS, Id: UL1 RR024992
  • Agency: NCRR NIH HHS, Id: UL1RR024992

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