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Scratch regulates neuronal migration onset via an epithelial-mesenchymal transition–like mechanism

Nature Neuroscience volume 16, pages 416–425 (2013)Cite this article

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Abstract

During neocortical development, the neuroepithelial or neural precursor cells that commit to neuronal fate need to delaminate and start migration toward the pial surface. However, the mechanism that couples neuronal fate commitment to detachment from the neuroepithelium remains largely unknown. Here we show that Scratch1 and Scratch2, members of the Snail superfamily of transcription factors, are expressed upon neuronal fate commitment under the control of proneural genes and promote apical process detachment and radial migration in the developing mouse neocortex. Scratch-induced delamination from the apical surface was mediated by transcriptional repression of the adhesion molecule E-cadherin. These findings suggest that Scratch proteins constitute a molecular link between neuronal fate commitment and the onset of neuronal migration. On the basis of their similarity to proteins involved in the epithelial-mesenchymal transition (EMT), we propose that Scratch proteins mediate the conversion of neuroepithelial cells to migrating neurons or intermediate neuronal progenitors through an EMT-related mechanism.

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Figure 1: Scratch1 and Scratch2 are expressed in newborn neurons and intermediate neuronal progenitors.
Figure 2: Scratch1 and Scratch2 are required for detachment of cells from the ventricular surface and the onset of radial migration.
Figure 3: Scratch1 and Scratch2 promote detachment of cells from the ventricular surface and the onset of radial migration.
Figure 4: Scratch1 and Scratch2 induce the onset of neuronal migration without enhancing neurogenesis.
Figure 5: Scratch1 inhibits E-cadherin expression.
Figure 6: Downregulation of E-cadherin promotes the onset of neuronal migration.
Figure 7: E-cadherin downregulation by Scratch1 triggers the onset of neuronal migration.

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Acknowledgements

We thank J.A. Cooper and R.N. Eisenman for critical reading of the manuscript; C.L. Cepko (Harvard University), T. Matsuda (Kyoto University), T. Kitamura (University of Tokyo), M. Nakafuku (University of Cincinnati), A. Nagafuchi (Kumamoto University), F. Matsuzaki (RIKEN Center for Developmental Biology), H. Okano (Keio University) and A. Garcia de Herreros (Institut Hospital del Mar d'Investigacions Mèdiques) for providing reagents; T. Sunabori for technical advice; H. Kosako and K. Ishiguro for generation of antibodies to Scratch1; Y. Hirabayashi, N. Masuyama, T. Yoshimatsu and T. Kato for technical assistance; K. Tyssowski for editing the manuscript; and members of the Gotoh laboratory for helpful discussion. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Neural Diversity and Neocortical Organization” from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, by CREST of the Japan Science and Technology Agency, and in part by the Global COE program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) of MEXT.

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  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

    Yasuhiro Itoh, Yasunobu Moriyama, Tsuyoshi Hasegawa & Yukiko Gotoh

  2. RIKEN Bioinformatics and Systems Engineering Division, Kanagawa, Japan

    Takaho A Endo & Tetsuro Toyoda

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  1. Yasuhiro Itoh
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Y.I., Y.M. and T.H. carried out the experiments and analyzed the data. T.A.E. and T.T. supported the analysis. Y.I. and Y.G. designed the study and wrote the manuscript. Y.G. supervised the study.

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Correspondence to Yasuhiro Itoh or Yukiko Gotoh.

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Itoh, Y., Moriyama, Y., Hasegawa, T. et al. Scratch regulates neuronal migration onset via an epithelial-mesenchymal transition–like mechanism. Nat Neurosci 16, 416–425 (2013). https://doi.org/10.1038/nn.3336

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