AMPK signaling in neuronal polarization: Putting the brakes on axonal traffic of PI3-Kinase

Neuronal polarization, the process by which neurons form multiple dendrites and an axon from the soma, is the first critical step in the formation and function of neural networks. Polarization begins with the rapid extension of a single neurite to produce an axon of impressive size and complex geometry, while the remaining sister neurites differentiate into dendrites. The extensive biosynthesis required to produce an axon therefore necessitates coordination with cellular energy status to ensure an ample energy supply. Our recent work shows that activity of the AMP-activated protein kinase (AMPK), the bio-energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells, plays an important role in the initiation of axonal growth. AMPK phosphorylates the cargo-binding light chain of the Kif5 motor protein, leading to dissociation of the phosphatidylinositol 3-Kinase (PI3K) from the motor complex. The mislocation of PI3K, which is normally enriched at the axonal tip for extension and differentiation, results in a lack of neurite specification and neuron polarization. These findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis, and suggest a novel cellular mechanism underlying the long-term neurological abnormalities as a consequence of bioenergy deficiency during early brain development.