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SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor

Nature Neuroscience volume 8, pages 1301–1309 (2005)Cite this article

Abstract

Axon growth is governed by the ability of growth cones to interpret attractive and repulsive guidance cues. Recent studies have shown that secreted signaling molecules known as morphogens can also act as axon guidance cues. Of the large family of Wnt signaling components, only Wnt4 and Wnt5 seem to participate directly in axon guidance. Here we show that secreted Frizzled-related protein 1 (SFRP1), a proposed Wnt signaling inhibitor, can directly modify and reorient the growth of chick and Xenopus laevis retinal ganglion cell axons. This activity does not require Wnt inhibition and is modulated by extracellular matrix molecules. Intracellularly, SFRP1 function requires Gα protein activation, protein synthesis and degradation, and it is modulated by cyclic nucleotide levels. Because SFRP1 interacts with Frizzled-2 (Fz2) and interference with Fz2 expression abolishes growth cone responses to SFRP1, we propose a previously unknown function for this molecule: the ability to guide growth cone movement via the Fz2 receptor.

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Figure 1: SFRP1 promotes neurite outgrowth in a dose-dependent manner.
Figure 2: Sfrp1 transcripts are distributed in critical regions of the developing chick visual pathway.
Figure 3: SFRP1 induces turning behavior in X. laevis growth cones, which is modulated by ECM.
Figure 4: Chick RGC axons respond to SFRP1 and to its CRD domain in stripe assays.
Figure 5: Exposure to SFRP1 interferes with the normal development of the optic tract.
Figure 6: RGC growth cone response to SFRP1 depends on the intracellular concentration of cAMP and cGMP and requires protein synthesis and proteasomal degradation.
Figure 7: SFRP1 binds to Fz2, and interference with Fz2 expression abolishes growth cone response to SFRP1.

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Acknowledgements

We sincerely thank M. Vetter and Z. Jianmin for their generous gift of Fz2 morpholinos, for providing suggestions and sharing their unpublished data. We are grateful to F. van Horck for help with the morpholino-injection technique. We thank B. Harris and I. Iordanova for helpful discussions and J. Borrell for providing help with statistical analysis. We thank I. Dompablo and C. Capitan for excellent technical assistance. This study was supported by grants from the Spanish Ministerio de Educación y Ciencia (BFU-2004-01585), the European Union (QLG3-CT-2001-01460) the Comunidad Autónoma de Madrid (08.5/0049.1/2003) and the Institutional RED CIEN (G03/06) to P.B. and by a Programme Grant from the Wellcome Trust (UK) to C.H. J.R. was supported by a Glaxo–Consejo Superior de Investigaciones Cientificas (CSIC) predoctoral fellowship, a European Molecular Biology Organization (EMBO) short-term fellowship and a 'Development' traveling award.

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Author notes

  1. Françoise Trousse

    Present address: Centre de Biologie du Développement, CNRS/UPS UMR 5547, Univ. P. Sabatier., 31062, Toulouse, Cedex 4, France

  2. Pilar Esteve and Christine Weinl: These authors contributed equally to this work.

Authors and Affiliations

  1. Departamento de Neurobiología del Desarrollo, Instituto Cajal, CSIC, Dr. Arce 37, Madrid, 28002, Spain

    Josana Rodriguez, Pilar Esteve, José María Ruiz, Yasmín Fermin, Françoise Trousse & Paola Bovolenta

  2. Department of Anatomy, Cambridge University, Downing Street, University of Cambridge, Cambridge, CB2 3DY, UK

    Christine Weinl, Asha Dwivedy & Christine Holt

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Supplementary information

Supplementary Fig. 1

Expression and purification of SFRP1 and its CRD and NTR domains. (PDF 154 kb)

Supplementary Fig. 2

Schematic representation of the Xenopus visual trajectory. (PDF 162 kb)

Supplementary Fig. 3

SFRP1 does not interfere with Wnt-induced neurite outgrowth in chick RGC. (PDF 117 kb)

Supplementary Fig. 4

SFRP1 mediated neurite outgrowth requires the activation of G proteins. (PDF 82 kb)

Supplementary Methods (PDF 75 kb)

Supplementary Note (PDF 14 kb)

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Rodriguez, J., Esteve, P., Weinl, C. et al. SFRP1 regulates the growth of retinal ganglion cell axons through the Fz2 receptor. Nat Neurosci 8, 1301–1309 (2005). https://doi.org/10.1038/nn1547

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