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The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF

Nature Cell Biology volume 9, pages 531–540 (2007)Cite this article

Abstract

FoxG1 is an evolutionarily conserved, winged-helix transcriptional repressor that maintains progenitor cells in the vertebrate forebrain. How the activity of FoxG1 is regulated is not known. Here, we report that in the developing Xenopus and mouse forebrain, FoxG1 is nuclear in progenitor cells but cytoplasmic in differentiating cells. The subcellular localisation of FoxG1 is regulated at the post-translational level by casein kinase I (CKI) and fibroblast growth factor (FGF) signalling. CKI phosphorylation of Ser 19 of FoxG1 promotes nuclear import, whereas FGF-induced phosphorylation of Thr 226 promotes nuclear export. Interestingly, FGF-induced phosphorylation of FoxG1 is mediated Akt kinase (also known as protein B kinase, PKB) kinase, rather than the MAPK pathway. Phosphorylation of endogenous FoxG1 is blocked by CKI and Akt inhibitors. In the mouse olfactory placode cell line OP27, and in cortical progenitors, increased FGF signalling causes FoxG1 to exit the nucleus and promotes neuronal differentiation, whereas FGF and Akt inhibitors block this effect. Thus, CKI and FGF signalling converge on an antagonistic regulation of FoxG1, which in turn controls neurogenesis in the forebrain.

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Figure 1: Expression of FoxG1 RNA and FoxG1 protein in the developing Xenopus and mouse forebrain.
Figure 2: FoxG1 is phosphorylated by CKIδ at the N-terminus.
Figure 3: FGF signalling induces the nuclear export of FoxG1.
Figure 4: FGF signalling induces the nuclear export of FoxG1 through the PI(3)K–Akt pathway.
Figure 5: Phosphorylation and subcellular localization of endogenous FoxG1.

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Acknowledgements

We thank K. Dorey and E. Amaya for discussions. N.P. is a Wellcome Trust Senior Research Fellow. T.R. was, and M.R. is, a Wellcome Trust Research Associate. This work was funded by the Wellcome Trust. N.I. and N.B. acknowledge support from the National Research Foundation and Medical Research Council of South Africa.

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Author notes

  1. Tarik Regad

    Present address: Current address: MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester, LE1 9HN, UK.,

  2. Martin Roth & Nancy Papalopulu

    Present address: Current address: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.,

  3. Nicholas Bredenkamp & Nicola Illing

    Present address: Current address: Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JQ, UK.,

Authors and Affiliations

  1. The Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QR, UK

    Tarik Regad, Martin Roth & Nancy Papalopulu

  2. Department of Physiology, Development and Neuroscience, Downing Site, University of Cambridge, Cambridge, CB2 3DY, UK

    Tarik Regad, Martin Roth & Nancy Papalopulu

  3. Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, 7700, South Africa

    Nicholas Bredenkamp

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Contributions

T.R. made the constructs, and performed and analysed all the biochemical and most immunostaining experiments. M.R. performed the in situ hybridizations. N.B. and N.I performed and analysed the OP27 experiments. N.P. planned the project, directed the research and wrote the manuscript.

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Correspondence to Nancy Papalopulu.

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The authors declare no competing financial interests.

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Supplementary Information Figure S1, S2, S3, S4, S5 and S6 (PDF 1157 kb)

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Regad, T., Roth, M., Bredenkamp, N. et al. The neural progenitor-specifying activity of FoxG1 is antagonistically regulated by CKI and FGF. Nat Cell Biol 9, 531–540 (2007). https://doi.org/10.1038/ncb1573

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