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An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice

Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites o...

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Autores principales: Tang, Maoxue, Park, Sarah H., Petri, Sabrina, Yu, Hang, Rueda, Carlos B., Abel, E. Dale, Kim, Carla Y., Hillman, Elizabeth M.C., Li, Fanghua, Lee, Yeojin, Ding, Lei, Jagadish, Smitha, Frankel, Wayne N., De Vivo, Darryl C., Monani, Umrao R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934852/
https://www.ncbi.nlm.nih.gov/pubmed/33351789
http://dx.doi.org/10.1172/jci.insight.145789
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author Tang, Maoxue
Park, Sarah H.
Petri, Sabrina
Yu, Hang
Rueda, Carlos B.
Abel, E. Dale
Kim, Carla Y.
Hillman, Elizabeth M.C.
Li, Fanghua
Lee, Yeojin
Ding, Lei
Jagadish, Smitha
Frankel, Wayne N.
De Vivo, Darryl C.
Monani, Umrao R.
author_facet Tang, Maoxue
Park, Sarah H.
Petri, Sabrina
Yu, Hang
Rueda, Carlos B.
Abel, E. Dale
Kim, Carla Y.
Hillman, Elizabeth M.C.
Li, Fanghua
Lee, Yeojin
Ding, Lei
Jagadish, Smitha
Frankel, Wayne N.
De Vivo, Darryl C.
Monani, Umrao R.
author_sort Tang, Maoxue
collection PubMed
description Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell–specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS.
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spelling pubmed-79348522021-03-09 An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice Tang, Maoxue Park, Sarah H. Petri, Sabrina Yu, Hang Rueda, Carlos B. Abel, E. Dale Kim, Carla Y. Hillman, Elizabeth M.C. Li, Fanghua Lee, Yeojin Ding, Lei Jagadish, Smitha Frankel, Wayne N. De Vivo, Darryl C. Monani, Umrao R. JCI Insight Research Article Paucity of the glucose transporter-1 (Glut1) protein resulting from haploinsufficiency of the SLC2A1 gene arrests cerebral angiogenesis and disrupts brain function to cause Glut1 deficiency syndrome (Glut1 DS). Restoring Glut1 to Glut1 DS model mice prevents disease, but the precise cellular sites of action of the transporter, its temporal requirements, and the mechanisms linking scarcity of the protein to brain cell dysfunction remain poorly understood. Here, we show that Glut1 functions in a cell-autonomous manner in the cerebral microvasculature to affect endothelial tip cells and, thus, brain angiogenesis. Moreover, brain endothelial cell–specific Glut1 depletion not only triggers a severe neuroinflammatory response in the Glut1 DS brain, but also reduces levels of brain-derived neurotrophic factor (BDNF) and causes overt disease. Reduced BDNF correlated with fewer neurons in the Glut1 DS brain. Controlled depletion of the protein demonstrated that brain pathology and disease severity was greatest when Glut1 scarcity was induced neonatally, during brain angiogenesis. Reducing Glut1 at later stages had mild or little effect. Our results suggest that targeting brain endothelial cells during early development is important to ensure proper brain angiogenesis, prevent neuroinflammation, maintain BDNF levels, and preserve neuron numbers. This requirement will be essential for any disease-modifying therapeutic strategy for Glut1 DS. American Society for Clinical Investigation 2021-02-08 /pmc/articles/PMC7934852/ /pubmed/33351789 http://dx.doi.org/10.1172/jci.insight.145789 Text en © 2021 Tang et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Tang, Maoxue
Park, Sarah H.
Petri, Sabrina
Yu, Hang
Rueda, Carlos B.
Abel, E. Dale
Kim, Carla Y.
Hillman, Elizabeth M.C.
Li, Fanghua
Lee, Yeojin
Ding, Lei
Jagadish, Smitha
Frankel, Wayne N.
De Vivo, Darryl C.
Monani, Umrao R.
An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title_full An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title_fullStr An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title_full_unstemmed An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title_short An early endothelial cell–specific requirement for Glut1 is revealed in Glut1 deficiency syndrome model mice
title_sort early endothelial cell–specific requirement for glut1 is revealed in glut1 deficiency syndrome model mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934852/
https://www.ncbi.nlm.nih.gov/pubmed/33351789
http://dx.doi.org/10.1172/jci.insight.145789
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