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GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling

Andy Willaert UGent, Sandeep Khatri, Bert Callewaert UGent, Paul Coucke UGent, Seth Crosby, Joseph Lee, Elaine Davis, Sruti Shiva, Michael Tsang and Anne De Paepe UGent, et al. (2012) HUMAN MOLECULAR GENETICS. 21(6). p.1248-1259
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- (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.
Please use this url to cite or link to this publication:
author
organization
alternative title
GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGF signaling
year
type
journalArticle (original)
publication status
published
subject
keyword
ANGIOTENSIN-II, ARTERIAL-TORTUOSITY-SYNDROME, CUTIS LAXA, GLUCOSE-TRANSPORTER, EXTRACELLULAR-MATRIX, HYPERTENSIVE-RATS, RECEPTOR KINASE, MARFAN-SYNDROME, ZEBRAFISH, MUTATIONS
journal title
HUMAN MOLECULAR GENETICS
Hum. Mol. Genet.
volume
21
issue
6
pages
1248 - 1259
Web of Science type
Article
Web of Science id
000300721300004
JCR category
GENETICS & HEREDITY
JCR impact factor
7.692 (2012)
JCR rank
13/161 (2012)
JCR quartile
1 (2012)
ISSN
0964-6906
DOI
10.1093/hmg/ddr555
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2044798
handle
http://hdl.handle.net/1854/LU-2044798
date created
2012-02-24 16:31:25
date last changed
2012-09-19 13:24:15
@article{2044798,
  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- (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.},
  author       = {Willaert, Andy and Khatri, Sandeep and Callewaert, Bert and Coucke, Paul and Crosby, Seth and Lee, Joseph and Davis, Elaine and Shiva, Sruti  and Tsang, Michael and De Paepe, Anne and Urban, Zsolt},
  issn         = {0964-6906},
  journal      = {HUMAN MOLECULAR GENETICS},
  keyword      = {ANGIOTENSIN-II,ARTERIAL-TORTUOSITY-SYNDROME,CUTIS LAXA,GLUCOSE-TRANSPORTER,EXTRACELLULAR-MATRIX,HYPERTENSIVE-RATS,RECEPTOR KINASE,MARFAN-SYNDROME,ZEBRAFISH,MUTATIONS},
  language     = {eng},
  number       = {6},
  pages        = {1248--1259},
  title        = {GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGF\ensuremath{\beta} signaling},
  url          = {http://dx.doi.org/10.1093/hmg/ddr555},
  volume       = {21},
  year         = {2012},
}

Chicago
Willaert, Andy, Sandeep Khatri, Bert Callewaert, Paul Coucke, Seth Crosby, Joseph Lee, Elaine Davis, et al. 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.
APA
Willaert, A., Khatri, S., Callewaert, B., Coucke, P., Crosby, S., Lee, J., Davis, E., et al. (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.
Vancouver
1.
Willaert A, Khatri S, Callewaert B, Coucke P, Crosby S, Lee J, et al. GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling. HUMAN MOLECULAR GENETICS. 2012;21(6):1248–59.
MLA
Willaert, Andy, Sandeep Khatri, Bert Callewaert, et al. “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 (2012): 1248–1259. Print.