GLUT1 deficiency links nutrient availability and apoptosis during embryonic development.
GLUT1 is essential for human brain development and function, as evidenced by the severe epileptic encephalopathy observed in children with GLUT1 deficiency syndrome resulting from inherited loss-of-function mutations in the gene encoding this facilitative glucose transporter. To further elucidate the pathophysiology of this disorder, the zebrafish orthologue of human GLUT1 was identified, and expression of this gene was abrogated during early embryonic development, resulting in a phenotype of aberrant brain organogenesis consistent with the observed expression of Glut1 in the embryonic tectum and specifically rescued by human GLUT1 mRNA. Affected embryos displayed impaired glucose uptake concomitant with increased neural cell apoptosis and subsequent ventricle enlargement, trigeminal ganglion cell loss, and abnormal hindbrain architecture. Strikingly, inhibiting expression of the zebrafish orthologue of the proapoptotic protein Bad resulted in complete rescue of this phenotype, and this occurred even in the absence of restoration of apparent glucose uptake. Taken together, these studies describe a tractable system for elucidating the cellular and molecular mechanisms of Glut1 deficiency and provide compelling in vivo genetic evidence directly linking nutrient availability and activation of mitochondria-dependent apoptotic mechanisms during embryonic brain development.
Jensen
Penny J
PJ
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Gitlin
Jonathan D
JD
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Carayannopoulos
Mary O
MO
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110. Electronic address: carayannopoulos@kids.wustl.edu.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003001:Cloning, Molecular; D003847:Deoxyglucose / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000172:deficiency* / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051272:Glucose Transporter Type 1; D029961:Zebrafish Proteins; C494818:badb protein, zebrafish; D051025:bcl-Associated Death Protein; D003847:Deoxyglucose; D005947:Glucose