title: SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis.
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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. pesteve@cbm.uam.es
authors.forename: Pilar
authors.initials: P
authors.lastname: Esteve
authors.forename: Africa
authors.initials: A
authors.lastname: Sandonìs
authors.forename: Marcos
authors.initials: M
authors.lastname: Cardozo
authors.forename: Jordi
authors.initials: J
authors.lastname: Malapeira
authors.forename: Carmen
authors.initials: C
authors.lastname: Ibañez
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Crespo
authors.forename: Severine
authors.initials: S
authors.lastname: Marcos
authors.forename: Sara
authors.initials: S
authors.lastname: Gonzalez-Garcia
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Toribio
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arribas
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.forename: Isabel
authors.initials: I
authors.lastname: Guerrero
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004330:Drosophila; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005123:Eye / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000196:embryology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D001973:Bromodeoxyuridine; D015820:Cadherins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051881:Receptor, Notch1; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C491628:Sfrp2 protein, mouse; C491234:Adam10 protein, mouse