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Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal

Nature Cell Biology volume 11, pages 873–880 (2009)Cite this article

An Erratum to this article was published on 01 August 2009

This article has been updated

Abstract

Epidermal growth factor-like domain 7 (EGFL7) is a secreted factor implicated in cellular responses such as cell migration and blood vessel formation; however the molecular mechanisms underlying the effects of EGFL7 are largely unknown. Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs. Such altered Notch signalling caused a shift in the differentiation pattern of cultured NSCs towards an excess of neurons and oligodendrocytes. We identified neurons as a source of EGFL7 in the brain, suggesting that brain-derived EGFL7 acts as an endogenous antagonist of Notch signalling that regulates proliferation and differentiation of subventricular zone-derived adult NSCs.

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Figure 1: EGFL7 binds to Notch receptors.
Figure 2: EGFL7 antagonizes canonical Notch1 signalling.
Figure 3: EGFL7 impairs NSC self-renewal.
Figure 4: EGFL7 is expressed in a subtype of neurons in the adult mouse brain.
Figure 5: EGFL7 affects NSC differentiation.

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Change history

  • 02 July 2009

    In the version of this article initially published online, the labelling of the yeast boxes in Fig. 1b was incorrect. In Fig. 1d the mNotch 2 values were missing, in Fig. 1g the Anti-EGFL7 was incorrectly labelled. In Fig 2c there was an extra ‘+’ sign. In Fig 3d the title was incorrect. In Fig 5b the BSA label was missing from under the fifth bar. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank all our colleagues who provided constructs. Thanks to Julio Granados, Yonathan Lissanu Deribe and Koraljka Husnjak for initial help with the yeast two-hybrid system. Thanks to Verdon Taylor for helpful suggestions, Ruth von Laer for help with FACS analysis and Stefan Momma and David G. McEwan for comments on the manuscript. This work was financially supported by the DFG within the SFB Transregio 23, subproject A4 and the Excellence Cluster Cardiopulmonary System, by the Adolf Messer Foundation, by the Paul and Ursula Klein Foundation, and an EMBO long-term fellowship granted to M.H.H.S. (ALTF 2003-881).

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Authors and Affiliations

  1. Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany

    Mirko H.H. Schmidt, Tanja Babuke, Srdjan Picuric, Werner Müller-Esterl & Ivan Dikic

  2. Institute of Neurology, Johann Wolfgang Goethe University School of Medicine, Heinrich-Hoffmann-Str. 7, D-60528, Frankfurt am Main, Germany

    Mirko H.H. Schmidt, Frank Bicker, Iva Nikolic, Jeannette Meister & Karl H. Plate

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Contributions

M.H.H.S. and I.D. designed experiments, analysed data and wrote the manuscript; I.D. supervised biochemical research; M.H.H.S. performed biochemical experiments and supervised neural and vascular experiments; F.B. worked on neurospheres and did IHC; I.N. and J.M. did experiments on D114 and HUVEC; T.B. did qRT-PCR; S.P. worked on protein purification; W.M.E. created EGFL7 antibodies and supported biochemical experiments; K.H.P. helped with experiments in brain and vasculature and all authors discsussed the results and commented on the manuscript.

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Correspondence to Mirko H.H. Schmidt or Ivan Dikic.

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Schmidt, M., Bicker, F., Nikolic, I. et al. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nat Cell Biol 11, 873–880 (2009). https://doi.org/10.1038/ncb1896

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