Editors' ChoiceNeuroscience

A New Dawn for Neurite Growth?

Science Signaling  15 Sep 2009:
Vol. 2, Issue 88, pp. ec306
DOI: 10.1126/scisignal.288ec306

Mori et al. have uncovered an unexpected role for the mitotic kinase Aurora A in neurite extension, a process that, like mitosis, depends on regulation of microtubule dynamics. In neurons, the protein NDEL1 interacts with the microtubule motor protein dynein, promoting neuronal growth and migration (see Lefkowitz and Gleeson). Thus, Mori et al., who previously showed that Aurora A phosphorylates NDEL1 to regulate microtubule organization during mitosis, looked to see whether Aurora A was present in postmitotic neurons. They found that Aurora A was indeed abundant in cultured dorsal root ganglion (DRG) neurons and, with its activated form (phosphorylated on T288), accumulated at the neurite hillock (the region where the DRG soma connects to the neurite). Phosphorylated NDEL1 colocalized with phosphorylated Aurora A at the hillock, as did the activated (phosphorylated on T410) form of atypical protein kinase C (aPKC)-ζ/λ, and phosphorylation of all three increased during neurite extension. Tagged forms of Aurora A and PKC-ζ were coimmunoprecipitated from COS-7 cells, and a combination of in vitro phosphorylation assay, mutational analysis, and mass spectrometry indicated that PKC-ζ phosphorylated Aurora A at T287, promoting its interaction with TPX2 (known to bind Aurora A) and its activation. Using phosphorylation-specific antibodies and a combination of techniques, including time-lapse microscopy, in vitro phosphorylation assay, mutational analysis, immunoprecipitation, and selective suppression of each of the major players, the authors determined that PKC-ζ and TPX2 functioned upstream of Aurora A, and NDEL1 downstream, to regulate microtubule dynamics and promote neurite extension. Thus, phosphorylation of NDEL1 by Aurora A appears to be crucial to regulating microtubule dynamics not only during mitosis but also during neurite extension.

D. Mori, M. Yamada, Y. Mimori-Kiyosue, Y. Shirai, A. Suzuki, S. Ohno, H. Saya, A. Wynshaw-Boris, S. Hirotsune, An essential role of the aPKC–Aurora A–NDEL1 pathway in neurite elongation by modulation of microtubule dynamics. Nat. Cell Biol. 11, 1057–1068 (2009). [PubMed]

G. K. Lefkowitz, J. G. Gleeson, Aurora A moonlights in neurite extension. Nat. Cell Biol. 11, 1053–1054 (2009). [PubMed]