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Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

Nature Neuroscience volume 12, pages 1373–1380 (2009)Cite this article

Abstract

The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non–cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

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Figure 1: Expression of Sip1 in the embryonic neocortex.
Figure 2: Sip1-deprived neocortex contains excessive numbers of upper layer neurons at the expense of deep layer neurons whilst maintaining their relative position within the neocortex.
Figure 3: Sip1 deletion in neocortical postmitotic cells causes premature generation of layer 2–5 neurons.
Figure 4: Enhanced astrocytic proliferation and premature and increased gliogenesis in Sip1 conditional mutants.
Figure 5: Ntf3 and Fgf9 steady-state mRNA levels are upregulated in the embryonic neocortex in the absence of Sip1.
Figure 6: Fgf9 can induce increased production of Olig2-expressing glial progenitors in wild-type forebrain slices in vitro.

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Acknowledgements

We thank the Flanders Institute for Biotechnology Microarray Facility, J. Allemeersch and P. Van Hummelen for their skillful analysis of our samples. We thank R. Hevner, D. Ornitz, L. Lei, J. Alberta and C. Stiles for reagents; P. Vanderhaeghen for advice and G. Fishell for numerous discussions. The D.H. laboratory thanks H. Van den Berghe for continuous support. E.S. was a postdoctoral fellow with the Research Foundation Flanders and the Franqui Foundation. This study was supported by the Research Foundation Flanders (G.0288.07), the inter-universitary attraction pole network (IUAP-PAI 6/20) and the EC-FP6 Project Endotrack (LSHG-CT-2006-19050). The V.T. laboratory was supported by Max-Planck Society, Heisenberg Program and Exc 257 of Deutsche Forschungsgemeinschaft, and Fritz Thyssen Foundation. A.N. was a Marie Curie Host Fellow For Early Stage Researchers Training (NEUREST MEST-CT-2004-504193).

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Author notes

  1. Eve Seuntjens and Anjana Nityanandam: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Biology (Celgen), Centre for Human Genetics, KULeuven, Leuven, Belgium

    Eve Seuntjens, Joke Debruyn, Agata Stryjewska & Danny Huylebroeck

  2. Department of Molecular and Developmental Genetics (VIB11), Flanders Institute for Biotechnology, Leuven, Belgium

    Eve Seuntjens, Joke Debruyn, Agata Stryjewska & Danny Huylebroeck

  3. Max-Planck-Institute for Experimental Medicine, Göttingen, Germany

    Anjana Nityanandam, Amaya Miquelajauregui, Sandra Goebbels, Klaus-Armin Nave & Victor Tarabykin

  4. Institute of Cell Biology and Neurobiology Charité–Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    Victor Tarabykin

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Contributions

E.S., A.N., A.M., D.H. and V.T. designed the experiments, E.S., A.N., A.M., J.D. and A.S. conducted the experiments, and S.G and K.-A.N. provided Nex-cre mice. V.T. wrote the manuscript and E.S., A.N. and D.H. edited the manuscript.

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Correspondence to Danny Huylebroeck or Victor Tarabykin.

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Seuntjens, E., Nityanandam, A., Miquelajauregui, A. et al. Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors. Nat Neurosci 12, 1373–1380 (2009). https://doi.org/10.1038/nn.2409

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