title: GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling.
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.
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
authors: Andy
authors: A
authors: Willaert
authors: Sandeep
authors: S
authors: Khatri
authors: Bert L
authors: BL
authors: Callewaert
authors: Paul J
authors: PJ
authors: Coucke
authors: Seth D
authors: SD
authors: Crosby
authors: Joseph G H
authors: JG
authors: Lee
authors: Elaine C
authors: EC
authors: Davis
authors: Sruti
authors: S
authors: Shiva
authors: Michael
authors: M
authors: Tsang
authors: Anne
authors: A
authors: De Paepe
authors: Zsolt
authors: Z
authors: Urban
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051246:Glucose Transport Proteins, Facilitative / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009672:Notochord / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics* / Q000254:growth & development
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D060172:Morpholinos; D018125:Receptors, Transforming Growth Factor beta; C568443:Slc2a10 protein, zebrafish; D016212:Transforming Growth Factor beta; D008156:Luciferases