RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity
RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity
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DOI：
10.1038/nn1922
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发表时间：
2007-07-01
影响因子：
25
通讯作者：
Takahashi, Chiaki
中科院分区：
文献类型：
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作者：
Muraguchi, Teruyuki;Takegami, Yujiro;Takahashi, Chiaki
我们报道，在小鼠胚胎的皮质发育过程中，带有Kazal基序的逆转诱导富含半胱氨酸的蛋白(RECK)通过拮抗由去整合素和金属蛋白酶结构域10(ADAM10)介导的Notch配体的胞外脱落来关键地调节Notch信号。在胚胎脑中，RECK特异性地表达于巢阳性神经前体细胞(NPC)。RECK缺陷的鼻咽癌细胞经历早熟分化，这与Nestin表达下调、Notch信号受损和自我更新缺陷有关。通过增强Notch信号或抑制内源性ADAM10活性，这些表型基本上得到了挽救。因此，我们发现RECK通过直接抑制ADAM10的蛋白分解活性来调节Notch配体的胞外结构域脱落。这一机制似乎对于Notch配体在相邻细胞中正确地诱导Notch信号是必不可少的。这些发现表明，RECK是ADAM10的生理抑制因子，ADAM10是Notch信号的上游调节因子，也是大脑发育的关键调节器。
We report that during cortical development in the mouse embryo, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) critically regulates Notch signaling by antagonizing the ectodomain shedding of Notch ligands, which is mediated by a disintegrin and metalloproteinase domain 10 (ADAM10). In the embryonic brain, RECK is specifically expressed in Nest-inpositive neural precursor cells (NPCs). Reck-deficient NPCs undergo precocious differentiation that is associated with downregulated Nestin expression, impaired Notch signaling and defective self-renewal. These phenotypes were substantially rescued either by enhancing Notch signaling or by suppressing endogenous ADAM10 activity. Consequently, we found that RECK regulates the ectodomain shedding of Notch ligands by directly inhibiting the proteolytic activity of ADAM10. This mechanism appeared to be essential for Notch ligands to properly induce Notch signaling in neighboring cells. These findings indicate that RECK is a physiological inhibitor of ADAM10, an upstream regulator of Notch signaling and a critical modulator of brain development.