Akt2 modulates glucose availability and downstream apoptotic pathways during development.
Glucose is the primary energy substrate for eukaryotic cells and the predominant substrate for the brain. Studies suggest that glucose serves an additional role in the regulation of cellular functions, including viability. Zebrafish is a tractable system for defining the cellular and molecular mechanisms perturbed by impaired glucose transport and metabolism. Previously, we demonstrated a critical role for the facilitative glucose transporter, Glut1, in the regulation of embryonic brain development. In this study, we aim to identify mediators in this Glut1-sensitive process by investigating the role of the antiapoptotic kinase, Akt2. Results show that abrogating expression of akt2 causes a phenotype strikingly similar to that observed when glut1 expression is inhibited. akt2-deficient embryos exhibit increased neuronal apoptosis, impaired glucose uptake, and death by 72 h postfertilization. Similar to what was observed in the glut1 morphants, inhibiting the expression of the proapoptotic protein, bad, in the context of impaired akt2 expression results in the inhibition of apoptosis and rescue of the morphant embryos. Intriguingly, overexpression of glut1 in the akt2 morphants was also able to rescue these embryos. Quantitative reverse transcription-PCR analysis revealed decreased glut1 transcript expression in akt2 morphant embryos. Taken together, these data suggest that Akt2 modulates glucose availability by regulating Glut1 expression at the transcript level. These data support a role for akt2 in an integrative pathway directly linking glucose, Glut1 expression, and activation of apoptosis and demonstrate the dependence of akt2 on glucose availability for the maintenance of cellular viability, particularly in the central nervous system.
Jensen
Penny J
PJ
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Gunter
Laura B
LB
Carayannopoulos
Mary O
MO
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002470:Cell Survival; D002490:Central Nervous System / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015027:Zebrafish
D051272:Glucose Transporter Type 1; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose