CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
Roles of the AMPK-Related Kinases NUAK1 and
NUAK2 Downstream of LKB1 during Cortical
Development
Julien Courchet 1 , Mariko Hirano 2 , Shinichi Aizawa 2 , Franck Polleux 1
1 The Scripps Research Institute, La Jolla, CA
2 Center for Developmental Institute, RIKEN, Kobe
Cortical development involves the coordinated migration of billions of neurons
and the establishment of axon/dendrite polarity underlying the the proper flow of
information transfer during the formation and function of neuronal circuits.
Impairment of these processes can lead to socially-devastating
neurodevelopmental defects such as autism spectrum disorders or mental
retardation. Our lab recently demonstrated that the activity of the polarity kinase
LKB1/STK11/Par4 is required and sufficient to induce neuron polarization and
axon specification, both in vitro and in vivo in part through its ability to activate
two members of the AMPK kinase family called SAD-A/B kinases (also called
BRSK1/2) (Barnes et al., Cell 2007). We now identified additional roles for
LKB1 involving two other distinct and poorly characterized downstream targets
of the AMPK-related kinase family, NUAK1 (ARK5/OMPHK1) and NUAK2
(SNARK/OMPHK2). NUAK1/2 kinases are highly enriched in the brain during
development and display specific, yet complimentary expression patterns in the
embryonic cortex. Simultaneous knockout of Nuak genes lead to severe
developmental abnormalities including exencephaly as well as impaired
neurogenesis and cell survival, indicating that NUAKs function is essential for
brain development. Using both in vitro and in vivo assays, we found that NUAK
kinases play a limited role downstream of LKB1 in the process of axon
specification, but are required later for proper axonal elongation and branching.
Finally, we obtained evidence suggesting that this new LKB1/NUAK pathway
mediate their function in axon growth in part by activating proteins required for
endocytosis, vesicular trafficking and autophagy. Overall, our results identify a
previously uncharacterized role of LKB1 in axon elongation and uncover a new
signaling pathway involving multiple kinases and potentially linking polarity
complexes to the regulation of axonal trafficking.
Presented by: Courchet, Julien
Poster No 022
Red Session
104