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

Hum Mol Genet. 2012 Mar 15;21(6):1248-59. doi: 10.1093/hmg/ddr555. Epub 2011 Nov 24.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cardiovascular Abnormalities / etiology*
  • Cardiovascular Abnormalities / metabolism
  • Cardiovascular Abnormalities / pathology
  • Glucose Transport Proteins, Facilitative / physiology*
  • Luciferases / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Molecular Sequence Data
  • Morpholinos / pharmacology
  • Mutation / genetics
  • Notochord / metabolism*
  • Notochord / pathology
  • Phenotype
  • Receptors, Transforming Growth Factor beta / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transcriptome
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*
  • Zebrafish / embryology*
  • Zebrafish / genetics*
  • Zebrafish / growth & development

Substances

  • Glucose Transport Proteins, Facilitative
  • Morpholinos
  • Receptors, Transforming Growth Factor beta
  • Slc2a10 protein, zebrafish
  • Transforming Growth Factor beta
  • Luciferases