SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

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Abstract

It is well established that retinal neurogenesis in mouse embryos requires the activation of Notch signaling, but is independent of the Wnt signaling pathway. We found that genetic inactivation of Sfrp1 and Sfrp2, two postulated Wnt antagonists, perturbs retinal neurogenesis. In retinas from Sfrp1−/−; Sfrp2−/− embryos, Notch signaling was transiently upregulated because Sfrps bind ADAM10 metalloprotease and downregulate its activity, an important step in Notch activation. The proteolysis of other ADAM10 substrates, including APP, was consistently altered in Sfrp mutants, whereas pharmacological inhibition of ADAM10 partially rescued the Sfrp1−/−; Sfrp2−/− retinal phenotype. Conversely, ectopic Sfrp1 expression in the Drosophila wing imaginal disc prevented the expression of Notch targets, and this was restored by the coexpression of Kuzbanian, the Drosophila ADAM10 homolog. Together, these data indicate that Sfrps inhibit the ADAM10 metalloprotease, which might have important implications in pathological events, including cancer and Alzheimer's disease.

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Figure 1: Neurogenesis is impaired in the central retina of Sfrp1−/−; Sfrp2−/− embryos.
Figure 2: Notch signaling is transiently upregulated in Sfrp1−/−; Sfrp2−/− retinas.
Figure 3: Inhibition of ADAM10 partially rescues the retinal phenotype of Sfrp1−/−; Sfrp2−/− embryos.
Figure 4: Sfrps interfere with ADAM10-mediated processing of N-cadherin and L1.
Figure 5: Sfrps interferes with ADAM10-mediated processing of APP.
Figure 6: Sfrps interacts with ADAM10.
Figure 7: Sfrp1 interacts with Kuz in Drosophila wing imaginal discs.

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Acknowledgements

We thank J.M. Ruiz for help with initial experiments and I. Dompablo for technical assistance, H. Bellen (Jan and Dan Duncan Neurological Research Institute), T. Tabata (University of Tokyo), S. Campuzano (CSIC–Universidad Autónoma de Madrid) and the Developmental Studies Hybridoma Bank for Drosophila antibodies and stocks, and A. Ludwig (RWTH Aachen University) for the G1254023X compound. This work was supported by grants from the Spanish MICINN (BFU2007-61774), Fundación Mutual Madrileña (2006-0916), Comunidad Autonoma de Madrid (P-SAL-0190-2006), Programa Intramural Especial–CSIC and CIBERER intramural funds to P.B.; CSIC intramural funds to P.E.; grants BFU2008-03320/BMC and CSD2007-00008 from the Spanish Ministerio de Ciencia e Innovación to I.G. and an institutional grant from Fundación Areces given to the Centro de Biología Molecular “Severo Ochoa” to I.G. and M.L.T.

Author information

P.E. and A. Sandonìs performed most of the immunohistochemical, in situ hybridization and western blot analysis. A. Shimono generated the Sfrp knockout mice. M.C. and I.C. performed immunoprecipitation and binding assays. J.M. and J.A. designed and performed APP shedding experiments in CHO cells. I.G. designed and performed (with C.I.) the assays in Drosophila. S.M. contributed Sfrp1 and Sfrp2 in situ hybridization localization. S.G.-G. and M.L.T. contributed expertise in Notch signaling and flow cytometry. P.B. and P.E. conceived and supervised the study and wrote the manuscript.

Correspondence to Pilar Esteve or Paola Bovolenta.

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