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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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.
The authors declare no competing financial interests.
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