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PMID:22116938

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Citation

Willaert, A, Khatri, S, Callewaert, BL, Coucke, PJ, Crosby, SD, Lee, JG, Davis, EC, Shiva, S, Tsang, M, De Paepe, A and Urban, Z (2012) GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. Hum. Mol. Genet. 21:1248-59

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.

Links

PubMed PMC3284116 Online version:10.1093/hmg/ddr555

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:GTR10

involved_in

GO:0030903: notochord development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120319-6

P

Seeded From UniProt

complete

DANRE:GTR10

involved_in

GO:0030903: notochord development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120319-5

P

Seeded From UniProt

complete

DANRE:GTR10

involved_in

GO:0072359: circulatory system development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120319-6

P

Seeded From UniProt

complete

DANRE:GTR10

involved_in

GO:0072359: circulatory system development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120319-5

P

Seeded From UniProt

complete


See also

References

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