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. (2012) GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. Human molecular genetics. 21(6):1248-1259.
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.