Editors' ChoiceNeuronal Development

Halting Mitochondria at Axonal Branch Points

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Sci. Signal.  02 Jul 2013:
Vol. 6, Issue 282, pp. ec150
DOI: 10.1126/scisignal.2004465

During embryonic development, pyramidal neurons of the cortex initially form a process that will become the apical dendritic tree and a process that will become the axon. The kinase LKB1 (also known as STK11, Par4) signals through the kinases SAD-A/B to specify the axon (see Satoh and Arber). Courchet et al. identified another LKB1 pathway, involving its downstream kinase effector NUAK1, that is necessary for the branching of the axon that occurs postnatally in the mouse developing cortex. Examination of pups 21 days after birth (P21) in which LKB1 was knocked out in the pyramidal neurons after axonal specification showed that the axons migrated properly but failed to form the branched phenotype typical of these neurons in the wild-type mice. Because NUAK1 is abundant in the embryonic and postnatal cortex, the authors knocked down NUAK1 in embryonic mouse brains and found that at P21 the axons exhibited a similar reduced branching phenotype as that observed in the LKB1 knockouts. Expression of NUAK1 with or without LKB1 in HeLa cells, which do not have LKB1, showed that NUAK1 abundance was increased when LKB1 was coexpressed. NUAK1 abundance and activity were decreased in cultured LKB1-knockout neurons. Knockdown of either NUAK1 or LKB1 in cultured neurons reduced axon length and branching, whereas overexpression of either protein increased axon length and branching. Tracking the movement of mitochondria in dissociated neurons showed that loss of either of the kinases NUAK1 or LKB1 or syntaphilin (an axonally targeted, microtubule- and mitochondria-binding protein) reduced the percentage of immobilized mitochondria, whereas overexpression of any of these proteins increased the fraction of immobile mitochondria along the axons. Overexpression of syntaphilin restored the immobile fraction of mitochondria to wild-type amounts and rescued axonal branching in dissociated LKB1-knockout neurons. LKB1- or NUAK1-deficient neurons had wild-type numbers of nascent presynaptic sites (defined by the presence of a tagged vesicular glutamate transporter) but had reduced colocalization of these sites with mitochondria compared with wild-type neurons. These results showed that LKB1 has a second later function in neuronal development. Early in development, LKB1 acts to specify axons; later, LKB1 functions to specify axon branching. This second process involves NUAK1 and possibly syntaphilin to signal mitochondria to stop at nascent presynaptic sites.

J. Courchet, T. L. Lewis Jr., S. Lee, V. Courchet, D.-Y. Liou, S. Aizawa, F. Polleux, Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture. Cell 153, 1510–1525 (2013). [PubMed]

D. Satoh, S. Arber, Carving axon arbors to fit: Master directs one kinase at a time. Cell 153, 1425-1426 (2013). [PubMed]