Journal
HUMAN MOLECULAR GENETICS
Volume 21, Issue 6, Pages 1248-1259Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr555
Keywords
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Funding
- National Institutes of Health [HL084922, HL090648]
- March of Dimes [1-FY09-402]
- Ghent University [BOF08/01M01108]
- Fighting Aneurysmal Disease (EC)
- NCI Cancer Center [P30 CA91842]
- ICTS/CTSA from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024992]
- NIH Roadmap for Medical Research
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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- (TGF) 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 TGF-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 TGF 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 TGF reporter gene activity. Finally, co-injection of antisense morpholinos targeting slc2a10 and smad7 (a TGF 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 TGF signaling.
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