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The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface

Nature Neuroscience volume 9, pages 1099–1107 (2006)Cite this article

Abstract

Stem cell persistence into adulthood requires self-renewal from early developmental stages. In the developing mouse brain, only apical progenitors located at the ventricle are self-renewing, whereas basal progenitors gradually deplete. However, nothing is known about the mechanisms regulating the fundamental difference between these progenitors. Here we show that the conditional deletion of the small Rho-GTPase cdc42 at different stages of neurogenesis in mouse telencephalon results in an immediate increase in basal mitoses. Whereas cdc42-deficient progenitors have normal cell cycle length, orientation of cell division and basement membrane contact, the apical location of the Par complex and adherens junctions are gradually lost, leading to an increasing failure of apically directed interkinetic nuclear migration. These cells then undergo mitoses at basal positions and acquire the fate of basal progenitors. Thus, cdc42 has a crucial role at the apical pole of progenitors, thereby regulating the position of mitoses and cell fate.

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Figure 1: Cdc42 localization and deletion by Emx1::Cre in the cerebral cortex.
Figure 2: Cell division and neurogenesis in the cerebral cortex of Emx1Cre/cdc42Δex2fl/fl mice.
Figure 3: Analysis of interkinetic nuclear migration.
Figure 4: Gradual loss of aderens junctions and Par complex in cdc42-deficient cortex.
Figure 5: Retraction of the radial process from the apical surface.
Figure 6: Molecular characteristics of progenitors in cdc42-deficient cortex.
Figure 7: Molecular markers for basal progenitors (SVZ) expand in the cdc42-deficient cortex.
Figure 8: Cell division and neurogenesis in the cerebral cortex after removal of cdc42 by hGFAP-Cre.

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Acknowledgements

We thank R.F. Hevner, D. Lin, D.J. Anderson, C. Schuurmans and V. Tarabykin for probes and antibodies; Y.-A. Barde for helpful comments on the manuscript; and M. Körbs, A. Bust, Z. Kirejczyk and B. DelGrande for excellent technical and secretarial assistance. M.G. is supported by the German Research Foundation. S.C. is recipient of a Marco Polo Fellowship.

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Authors and Affiliations

  1. GSF, National Research Center for Environment and Health, Institute for Stem Cell Research, Ingolstädter Landstraße 1, Neuherberg, D–85764, Munich, Germany

    Silvia Cappello, Hanna M Eilken, Michael A Rieger, Timm T Schroeder & Magdalena Götz

  2. Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden, D-01307, Germany

    Alessio Attardo, Michaela Wilsch-Bräuninger & Wieland B Huttner

  3. Institute of Molecular Pathology, Faculty of Health Sciences, University of Copenhagen, Frederik V's Vej 11, Copenhagen, DK-2100, Denmark

    Xunwei Wu & Cord Brakebusch

  4. Laboratory for Behavioral Genetics, RIKEN Brain Science Institute (BSI), 2-1 Hirosawa, Wako-shi, 351-0198, Saitama, Japan

    Takuji Iwasato & Shigeyoshi Itohara

  5. Institute of Physiology, University of Munich, Schillerstrasse 46, Munich, 80336, Germany

    Magdalena Götz

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Contributions

S.C. did most of the experimental work. A.A. did the electroporation analysis. X.W. and C.B. generated the floxed cdc42 mice. T.I. and S.I. generated the Emx1::cre mice. M.W.-B. did the electronmicroscopic analysis. H.M.E., M.A.R. and T.T.S. taught and helped with the time-lapse analysis. W.B.H. was involved in writing the manuscript and designing experiments. M.G. designed the entire project, directed most of the experiments and wrote the manuscript together with S.C.

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Correspondence to Magdalena Götz.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Phenotype of the adult cdc42-deficient cortex. (PDF 391 kb)

Supplementary Fig. 2

Analysis of orientation of cell division and cell cycle. (PDF 75 kb)

Supplementary Fig. 3

Distribution pattern of BrdU-labeled cells after S-phase. (PDF 184 kb)

Supplementary Fig. 4

Analysis of basal lamina, radial processes and adherens junctions after cdc42 deletion at E10. (PDF 843 kb)

Supplementary Video 1

Example 1 of a cortical neuroepithelial cell isolated at embryonic day 12 from cdc42-deficient cortex exhibiting interkinetic nuclear migration in vitro. See Methods for details. (AVI 958 kb)

Supplementary Video 2

Example 2 of a cortical neuroepithelial cell isolated at embryonic day 12 from cdc42-deficient cortex exhibiting interkinetic nuclear migration in vitro. See Methods for details. (AVI 2536 kb)

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Cappello, S., Attardo, A., Wu, X. et al. The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface. Nat Neurosci 9, 1099–1107 (2006). https://doi.org/10.1038/nn1744

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