Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Nat Neurosci. 2011 May;14(5):562-9. doi: 10.1038/nn.2794. Epub 2011 Apr 10.
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.
已经证实，小鼠胚胎中的视网膜神经发生需要 Notch 信号的激活，但不依赖于 Wnt 信号通路。我们发现，两种假定的 Wnt 拮抗剂 Sfrp1 和 Sfrp2 的基因失活会干扰视网膜神经发生。在 Sfrp1(-/-); Sfrp2(-/-) 胚胎的视网膜中，Notch 信号短暂上调，因为 Sfrps 结合 ADAM10 金属蛋白酶并下调其活性，这是 Notch 激活的重要步骤。Sfrp 突变体中其他 ADAM10 底物的蛋白水解作用始终发生改变，而 ADAM10 的药理学抑制部分挽救了 Sfrp1(-/-); Sfrp2(-/-) 视网膜表型。相反，果蝇翅 imaginal 盘中的外源性 Sfrp1 表达阻止了 Notch 靶基因的表达，而果蝇 ADAM10 同源物 Kuzbanian 的共表达则恢复了这种表达。总之，这些数据表明 Sfrps 抑制 ADAM10 金属蛋白酶，这可能对包括癌症和阿尔茨海默病在内的病理事件具有重要意义。
