Mammalian glycogen synthase kinase-3 (GSK-3), a critical regulator in neuronal signaling, cognition, and behavior, exists as two isozymes GSK-3α and GSK-3β. Their distinct biological functions remains largely unknown. Here, we examined the evolutionary significance of each of these isozymes. Surprisingly, we found that unlike other vertebrates that harbor both GSK-3 genes, the GSK-3α gene is missing in birds. GSK-3-mediated tau phosphorylation was significantly lower in adult bird brains than in mouse brains, a phenomenon that was reproduced in GSK-3α knockout mouse brains. Tau phosphorylation was detected in brains from bird embryos suggesting that GSK-3 isozymes play distinct roles in tau phosphorylation during development. Birds are natural GSK-3α knockout organisms and may serve as a novel model to study the distinct functions of GSK-3 isozymes.
Bibliographical noteFunding Information:
This work was supported by FP7 EU Grant #223276 “NeuroGSK3” and the Israeli Academy of Sciences , Grant #341/10 . JR Woodgett acknowledge Grant CIHR MOP#74711. We thank Dr. Tal Pupko for helpful discussions. We apologize to investigators whose work could not be cited because of space limitations.
- Tau phosphorylation