GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling
- Authors
- Willaert, A., Khatri, S., Callewaert, B.L., Coucke, P.J., Crosby, S.D., Lee, J.G., Davis, E.C., Shiva, S., Tsang, M., De Paepe, A., and Urban, Z.
- ID
- ZDB-PUB-111129-35
- Date
- 2012
- Source
- Human molecular genetics 21(6): 1248-1259 (Journal)
- Registered Authors
- Tsang, Michael, Urban, Zsolt
- Keywords
- none
- Datasets
- GEO:GSE34510, GEO:GSE34509, GEO:GSE34508
- 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
- PubMed
- 22116938 Full text @ Hum. Mol. Genet.
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 if 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, that was coupled with 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 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/glut10 and smad7 (a TGFβ inhibitor) resulted in a partial rescue of smad7 morphant phenotypes, suggesting scl2a10/glut10 functions downstream of smads. Taken together, scl2a10/glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFβ signaling.