Terminal Axon Branching Is Regulated by the LKB1-NUAK1 Kinase Pathway via Presynaptic Mitochondrial Capture

Abstract

SUMMARY The molecular mechanisms underlying the axon arborization of mammalian neurons are poorly understood but are critical for the establishment of functional neural circuits. We identified a pathway defined by two kinases, LKB1 and NUAK1, required for cortical axon branching in vivo. Conditional deletion of LKB1 after axon specification or knockdown of NUAK1 drastically reduced axon branching in vivo whereas their overexpression was sufficient to increase axon branching. The LKB1-NUAK1 pathway controls mitochondria immobilization in axons. Using manipulation of Syntaphilin, a protein necessary and sufficient to arrest mitochondrial transport specifically in the axon, we demonstrate that the LKB1-NUAK1 kinase pathway regulates axon branching by promoting mitochondria immobilization. Finally, we show that LKB1 and NUAK1 are necessary and sufficient to immobilize mitochondria specifically at nascent presynaptic sites. Our results unravel a link between presynaptic mitochondrial capture and axon branching.

Investigating CNS synaptogenesis at single-synapse resolution by combining reverse genetics with correlative light and electron microscopy

“…3J-L). This is in good agreement with the requirement for mitochondria to provide energy throughout the large volume of the axon and to presynaptic active zones (Vos et al, 2010), and is also consistent with proposed roles for mitochondria in axon branch formation (Courchet et al, 2013). Fig.…”

Mitochondria dynamism: of shape, transport and cell migration

“…and also able to arrest their transport along the axons [84]. Recently, for example, it has been demonstrated that the mitochondrial immobilization, via the LKB1-NUAK1 kinase pathway, is particularly important for axon branching at nascent presynaptic sites [85]. However, whether or not LKB1-NUAK1 interact with SYNTAPHILIN to promote axon branching has still to be investigated.…”

Micromanagement with light

“…Organelle location can even affect a cell's shape. Neurons send out projections called axons to transmit impulses to other neurons, and axons tend to branch into two at spots where mitochondria, the cell's energy facility, have settled 3,4 . However, the effects of cellular layout can be difficult to unravel.…”