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Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate

Abstract

Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1−/− (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1−/− mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development.

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Figure 1: SP600125 increases the rate of neuronal migration.
Figure 2: Active JNK1 retards neuronal migration.
Figure 3: Cortical layer formation is advanced in Jnk1−/− mice.
Figure 4: Cytoplasmic JNK retards neuronal migration in developing brain but nuclear JNK enhances it.
Figure 5: SCG10 has a requisite role in neuronal migration, increasing soluble tubulin pools and forward movement of neurons.
Figure 6: JNK1-site phosphorylated SCG10 rescues a normal migration phenotype in Jnk1−/− brain.
Figure 7: Jnk1−/− neurons leave the multipolar stage sooner and migrate faster.

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Acknowledgements

We thank T. Herdegen for mice for pilot experiments. This work was supported by grants from the Academy of Finland (218125, 125860, 206497, 111870, 203520 and 110445), Turku Graduate School of Biomedical Sciences, the Finnish Graduate School of Neuroscience, Magnus Ehrnrooth's Foundation, FP6 STRESSPROTECT and Åbo Akademi University. T.K. was supported by the Danish Cancer Society. L.N. is funded by Walloon Excellence in Lifesciences and Biotechnology.

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N.W., J.Z., A.P., B.B., E.K., E.R. and T.T. designed and carried out the experiments. C.G.-F., T.K., J.S., L.N. and M.J.C. provided technical training and advice. E.T.C. designed and supervised the project and wrote the manuscript.

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Correspondence to Eleanor T Coffey.

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Westerlund, N., Zdrojewska, J., Padzik, A. et al. Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate. Nat Neurosci 14, 305–313 (2011). https://doi.org/10.1038/nn.2755

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