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α2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2

Abstract

Disrupted cortical neuronal migration is associated with epileptic seizures and developmental delay. However, the molecular mechanism by which disruptions of early cortical development result in neurological symptoms is poorly understood. Here we report α2-chimaerin as a key regulator of cortical neuronal migration and function. In utero suppression of α2-chimaerin arrested neuronal migration at the multipolar stage, leading to accumulation of ectopic neurons in the subcortical region. Mice with such migration defects showed an imbalance between excitation and inhibition in local cortical circuitry and greater susceptibility to convulsant-induced seizures. We further show that α2-chimaerin regulates bipolar transition and neuronal migration through modulating the activity of CRMP-2, a microtubule-associated protein. These findings establish a new α2-chimaerin-dependent mechanism underlying neuronal migration and proper functioning of the cerebral cortex and provide insights into the pathogenesis of seizure-related neurodevelopmental disorders.

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Figure 1: α2-chimaerin is essential for neuronal migration during neocortex development.
Figure 2: α2-chimaerin regulates multipolar-bipolar transition.
Figure 3: α2-chimaerin knockdown results in accumulations of ectopic neurons in postnatal brain.
Figure 4: Mice with in utero suppression of α2-chimaerin show altered cortical excitability and show enhanced susceptibility to seizures.
Figure 5: The SH2 domain of α2-chimaerin is required for neuronal migration.
Figure 6: α2-chimaerin mediates neurotrophin-dependent regulation of CRMP-2 activity.
Figure 7: α2-chimaerin mediates neuronal migration through precise regulation of CRMP-2 activity.

References

  1. Guerrini, R., Sicca, F. & Parmeggiani, L. Epilepsy and malformations of the cerebral cortex. Epileptic Disord. 5 (suppl. 2), S9–S26 (2003).

    PubMed  Google Scholar 

  2. Chang, B.S. & Walsh, C.A. The genetic basis of human cerebral cortical malformations. in Principles of Molecular Medicine Vol. XIII (eds. Runge, M.S. and Patterson, C.) 1073–1079 (Humana, 2006).

  3. Ayala, R., Shu, T. & Tsai, L.H. Trekking across the brain: the journey of neuronal migration. Cell 128, 29–43 (2007).

    Article  CAS  Google Scholar 

  4. Valiente, M. & Marin, O. Neuronal migration mechanisms in development and disease. Curr. Opin. Neurobiol. 20, 68–78 (2010).

    Article  CAS  Google Scholar 

  5. Gleeson, J.G. & Walsh, C.A. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci. 23, 352–359 (2000).

    Article  CAS  Google Scholar 

  6. Deutsch, S.I., Burket, J.A. & Katz, E. Does subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications. Eur. Neuropsychopharmacol. 20, 281–287 (2010).

    Article  CAS  Google Scholar 

  7. Singh, K.K. et al. Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Neuron 67, 33–48 (2010).

    Article  CAS  Google Scholar 

  8. Wegiel, J. et al. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 119, 755–770 (2010).

    Article  Google Scholar 

  9. Nadarajah, B., Alifragis, P., Wong, R.O. & Parnavelas, J.G. Neuronal migration in the developing cerebral cortex: observations based on real-time imaging. Cereb. Cortex 13, 607–611 (2003).

    Article  CAS  Google Scholar 

  10. Noctor, S.C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A.R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136–144 (2004).

    Article  CAS  Google Scholar 

  11. LoTurco, J.J. & Bai, J. The multipolar stage and disruptions in neuronal migration. Trends Neurosci. 29, 407–413 (2006).

    Article  CAS  Google Scholar 

  12. Tabata, H. & Nakajima, K. Multipolar migration: the third mode of radial neuronal migration in the developing cerebral cortex. J. Neurosci. 23, 9996–10001 (2003).

    Article  CAS  Google Scholar 

  13. Kawauchi, T. & Hoshino, M. Molecular pathways regulating cytoskeletal organization and morphological changes in migrating neurons. Dev. Neurosci. 30, 36–46 (2008).

    Article  CAS  Google Scholar 

  14. Hall, C. et al. alpha2-chimaerin, a Cdc42/Rac1 regulator, is selectively expressed in the rat embryonic nervous system and is involved in neuritogenesis in N1E–115 neuroblastoma cells. J. Neurosci. 21, 5191–5202 (2001).

    Article  CAS  Google Scholar 

  15. Iwasato, T. et al. Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell 130, 742–753 (2007).

    Article  CAS  Google Scholar 

  16. Beg, A.A., Sommer, J.E., Martin, J.H. & Scheiffele, P. alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron 55, 768–778 (2007).

    Article  CAS  Google Scholar 

  17. Wegmeyer, H. et al. EphA4-dependent axon guidance is mediated by the RacGAP alpha2-chimaerin. Neuron 55, 756–767 (2007).

    Article  CAS  Google Scholar 

  18. Shi, L. et al. Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc. Natl. Acad. Sci. USA 104, 16347–16352 (2007).

    Article  CAS  Google Scholar 

  19. Miyake, N. et al. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science 321, 839–843 (2008).

    Article  CAS  Google Scholar 

  20. Bacchelli, E. et al. Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol. Psychiatry 8, 916–924 (2003).

    Article  CAS  Google Scholar 

  21. Lencz, T. et al. Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. Proc. Natl. Acad. Sci. USA 104, 19942–19947 (2007).

    Article  CAS  Google Scholar 

  22. Davidsson, J., Collin, A., Olsson, M.E., Lundgren, J. & Soller, M. Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: an array-based genotype-phenotype correlation and a comprehensive review of previously published cases. Epilepsy Res. 81, 69–79 (2008).

    Article  CAS  Google Scholar 

  23. Jacobs, K.M., Kharazia, V.N. & Prince, D.A. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res. 36, 165–188 (1999).

    Article  CAS  Google Scholar 

  24. Ackman, J.B. et al. Abnormal network activity in a targeted genetic model of human double cortex. J. Neurosci. 29, 313–327 (2009).

    Article  CAS  Google Scholar 

  25. Manent, J.B., Wang, Y., Chang, Y., Paramasivam, M. & LoTurco, J.J. Dcx reexpression reduces subcortical band heterotopia and seizure threshold in an animal model of neuronal migration disorder. Nat. Med. 15, 84–90 (2009).

    Article  CAS  Google Scholar 

  26. Hall, C., Lim, L. & Leung, T. C1, see them all. Trends Biochem. Sci. 30, 169–171 (2005).

    Article  CAS  Google Scholar 

  27. North, H.A. et al. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling. Development 136, 2467–2476 (2009).

    Article  CAS  Google Scholar 

  28. Torii, M., Hashimoto-Torii, K., Levitt, P. & Rakic, P. Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461, 524–528 (2009).

    Article  CAS  Google Scholar 

  29. Ohmiya, M. et al. Brain-derived neurotrophic factor alters cell migration of particular progenitors in the developing mouse cerebral cortex. Neurosci. Lett. 317, 21–24 (2002).

    Article  CAS  Google Scholar 

  30. Medina, D.L. et al. TrkB regulates neocortex formation through the Shc/PLCgamma-mediated control of neuronal migration. EMBO J. 23, 3803–3814 (2004).

    Article  CAS  Google Scholar 

  31. Fukumitsu, H. et al. Brain-derived neurotrophic factor participates in determination of neuronal laminar fate in the developing mouse cerebral cortex. J. Neurosci. 26, 13218–13230 (2006).

    Article  CAS  Google Scholar 

  32. Zhao, C.T. et al. PKCdelta regulates cortical radial migration by stabilizing the Cdk5 activator p35. Proc. Natl. Acad. Sci. USA 106, 21353–21358 (2009).

    Article  CAS  Google Scholar 

  33. Fukata, Y. et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat. Cell Biol. 4, 583–591 (2002).

    Article  CAS  Google Scholar 

  34. Yoshimura, T. et al. GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120, 137–149 (2005).

    Article  CAS  Google Scholar 

  35. Marín, O., Valiente, M., Ge, X. & Tsai, L.H. Guiding neuronal cell migrations. Cold Spring Harb. Perspect. Biol. 2, a001834 (2010).

    Article  Google Scholar 

  36. Bai, J. et al. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat. Neurosci. 6, 1277–1283 (2003).

    Article  CAS  Google Scholar 

  37. Tsai, J.W., Chen, Y., Kriegstein, A.R. & Vallee, R.B. LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J. Cell Biol. 170, 935–945 (2005).

    Article  CAS  Google Scholar 

  38. Ohshima, T. et al. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development 134, 2273–2282 (2007).

    Article  CAS  Google Scholar 

  39. Arimura, N., Menager, C., Fukata, Y. & Kaibuchi, K. Role of CRMP-2 in neuronal polarity. J. Neurobiol. 58, 34–47 (2004).

    Article  CAS  Google Scholar 

  40. Brown, M. et al. Alpha2-chimaerin, cyclin-dependent kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J. Neurosci. 24, 8994–9004 (2004).

    Article  CAS  Google Scholar 

  41. Pawson, T. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 116, 191–203 (2004).

    Article  CAS  Google Scholar 

  42. Bar, I., Lambert de Rouvroit, C. & Goffinet, A.M. The Reelin signaling pathway in mouse cortical development. Eur. J. Morphol. 38, 321–325 (2000).

    Article  CAS  Google Scholar 

  43. Young-Pearse, T.L. et al. A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J. Neurosci. 27, 14459–14469 (2007).

    Article  CAS  Google Scholar 

  44. Chen, G. et al. Semaphorin-3A guides radial migration of cortical neurons during development. Nat. Neurosci. 11, 36–44 (2008).

    Article  Google Scholar 

  45. Lapray, D. et al. Spontaneous epileptic manifestations in a DCX knockdown model of human double cortex. Cereb. Cortex 20, 2694–2701 (2010).

    Article  Google Scholar 

  46. Thomas, E.A. et al. Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol. Psychiatry 8, 983–93, 950 (2003).

    Article  CAS  Google Scholar 

  47. Lo, K.Y. et al. SLAM-associated protein as a potential negative regulator in Trk signaling. J. Biol. Chem. 280, 41744–41752 (2005).

    Article  CAS  Google Scholar 

  48. Itoh, Y., Masuyama, N., Nakayama, K., Nakayama, K.I. & Gotoh, Y. The cyclin-dependent kinase inhibitors p57 and p27 regulate neuronal migration in the developing mouse neocortex. J. Biol. Chem. 282, 390–396 (2007).

    Article  CAS  Google Scholar 

  49. Racine, R.J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294 (1972).

    Article  CAS  Google Scholar 

  50. Fu, W.Y. et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10, 67–76 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to C. Hall (University College London) for α2-chimaerin constructs, antibody and CRMP-2 constructs; K. Kaibuchi (Nagoya University Graduate School of Medicine) for pCRMP-2 (Thr514) antibody; and T. Matsuda and C.L. Cepko (Harvard Medical School) for pCAG vectors. We thank N. Brose and T. Marquardt (Max Planck Institute) for providing Chn1−/− mice. We thank K.-O. Lai and Z. Cheung for critical reading of the manuscript and members of the Ip laboratory for discussions. We also thank C. Kwong, H.W. Tsang, Y. Dai, B. Butt, T. Ye and K. Ho for technical assistance. This study was supported in part by the Research Grants Council of Hong Kong (HKUST 661007, 660808, 660610 and 660110), the Area of Excellence Scheme of the University Grants Committee (AoE/B-15/01) and the Hong Kong Jockey Club. J.P.K.I. and N.Y.I. are recipients of a Croucher Foundation Research Studentship and Croucher Foundation Senior Research Fellowship, respectively.

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Authors and Affiliations

Authors

Contributions

N.Y.I. supervised the project. J.P.K.I., L.S., Y.C., W.-Y.F., A.K.Y.F. and N.Y.I. designed the experiments. J.P.K.I. and L.S. conducted the majority of experiments. J.P.K.I., L.S., Y.C., A.K.Y.F. and N.Y.I. performed the data analyses. Y.I. and Y.G. provided technical support on in utero electroporation and live-imaging experiments. J.P.K.I. and Y.I. performed live-imaging experiments. W.-H.Y. performed the electrophysiology experiments and subsequent data analyses. A.B. provided Chn1−/− mice. J.P.K.I., L.S., A.K.Y.F. and N.Y.I. wrote the manuscript.

Corresponding author

Correspondence to Nancy Y Ip.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 1711 kb)

Supplementary Video 1

This movie shows the migration of neurons electroporated with pSUPER vector and GFP plasmids. Most of the neurons attained bipolar shape, underwent nuclear translocation and migrated up to the cortical plate. Images were captured every 15 min for 13 h. (MOV 606 kb)

Supplementary Video 2

This movie shows the migration of neurons electroporated with α2-chimerin shRNA and GFP plasmids. α2-chimerin knockdown neurons were unable to enter into the cortical plate, and showed local movement within the intermediate zone. Images were captured every 15 min for 13 h. (MOV 588 kb)

Supplementary Video 3

This movie shows an example of migrating neurons electroporated with pSUPER vector and GFP plasmids. The neuron extended and retracted neurites actively, and eventually formed one major leading process guiding the migration of cell body towards pial surface. Images were captured every 10 min for 7 h. (MOV 587 kb)

Supplementary Video 4

This movie shows an example of migrating neurons electroporated with α2-chimerin shRNA and GFP plasmids. The neuron showed impaired neurite dynamics and failed to form a leading process towards pial surface. Images were captured every 10 min for 7 h. (MOV 609 kb)

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Ip, J., Shi, L., Chen, Y. et al. α2-chimaerin controls neuronal migration and functioning of the cerebral cortex through CRMP-2. Nat Neurosci 15, 39–47 (2012). https://doi.org/10.1038/nn.2972

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