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

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

Authors

  • Willaert A
  • Khatri S
  • Callewaert BL
  • Coucke PJ
  • Crosby SD
  • Lee JG
  • Davis EC
  • Shiva S
  • Tsang M
  • De Paepe A
  • Urban Z

Journal

Human molecular genetics

Publication Data

March 15, 2012

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

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