Document Type
Article
Publication Date
2011
Abstract
Mammalian brain connectivity requires the coordinated production and migration of billions of neurons and the formation of axons and dendrites. The LKB1/Par4 kinase is required for axon formation during cortical development in vivo partially through its ability to activate SAD-A/B kinases. LKB1 is a master kinase phosphorylating and activating at least 11 other serine/threonine kinases including the metabolic sensor AMP-activated protein kinase (AMPK), which defines this branch of the kinome. A recent study using a gene-trap allele of the β1 regulatory subunit of AMPK suggested that AMPK catalytic activity is required for proper brain development including neurogenesis and neuronal survival. We used a genetic loss-of-function approach producing AMPKα1/α2-null cortical neurons to demonstrate that AMPK catalytic activity is not required for cortical neurogenesis, neuronal migration, polarization, or survival. However, we found that application of metformin or AICAR, potent AMPK activators, inhibit axogenesis and axon growth in an AMPK-dependent manner. We show that inhibition of axon growth mediated by AMPK overactivation requires TSC1/2-mediated inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. Our results demonstrate that AMPK catalytic activity is not required for early neural development in vivo but its overactivation during metabolic stress impairs neuronal polarization in a mTOR-dependent manner.
Editor
Yuh-Nung Jan
DOI
10.1073/pnas.1013660108
Publisher
National Academy of Sciences
Repository Citation
Williams, T., Courchet, J., Viollet, B., Brenman, J., & Polleux, F. (2011). AMPK kinase activity is not required for neuronal development but regulates axogenesis during metabolic stress. PNAS, 108(14), 5849-54. https://doi.org/10.1073/pnas.1013660108
Publication Information
Proceedings of the National Academy of Sciences of the United States of America
Comments
Author contributions: T.W., J.C., J.E.B., and F.P. designed research; T.W. and J.C. performed research; T.W., J.C., and B.V. contributed new reagents/analytic tools; T.W., J.C., J.E.B., and F.P. analyzed data; and T.W., J.C., J.E.B., and F.P. wrote the paper.