The building of functioning neural circuits is highly dependent on glucose metabolism to ensure energy-demanding neuronal functions such as synaptic activity or long-distance axonal transport. Deregulation of the energy metabolism and mitochondrial function has been linked to neurodevelopmental conditions such as Autism Spectrum Disorders (ASD). However, our current understanding of metabolic regulation in the developing brain and in particular in rapidly growing neurons is still fragmental.
The correct patterning of long-range axonal connections relies on the coordinated activation of cell-intrinsic signaling pathways in response to environmental cues such as trophic factors, guidance molecules and synaptic activity. The kinase LKB1 has been linked to several aspects of axon development through the sequential activation of intracellular signaling pathways involving AMPK and related kinases. We previously identified that LKB1 regulates axon outgrowth and terminal branching through the activation of NUAK1, an AMPK-related kinase whose mutations are associated to ASD and other neurodevelopmental disorders. NUAK1, but not AMPK, regulates axonal mitochondria trafficking and metabolic activity to support axonal branching, in part through the regulation of a mitochondrial microprotein. We furthermore describe the LKB1/NUAK1 axis as an integrator of extracellular cues controlling axon branching, providing neural correlates to behavioral alterations found in LKB1- and NUAK1-deficient mice. Overall, our results suggest that LKB1 integrates extracellular signals to adapt axon branching to the local cellular context and suggest that a local regulation of metabolic activity participates in the balance between short and long-range axonal projections.