Presenilin-dependent γ-secretase activity modulates thymocyte development
Presenilin-dependent γ-secretase activity modulates thymocyte development
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DOI：
10.1073/pnas.161102498
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发表时间：
2001-07-31
影响因子：
11.1
通讯作者：
Perlmutter, RM
中科院分区：
文献类型：
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作者：
Doerfler, P;Shearman, MS;Perlmutter, RM
在神经元细胞中，早老素依赖的γ分泌酶活性裂解淀粉样蛋白前体蛋白以释放A -肽，并催化胞内跨膜受体Notch的释放。异常A β肽的积累似乎与阿尔茨海默病有因果关系。因此，抑制β肽的产生是治疗干预的潜在目标。Notch蛋白在许多不同生物体和不同发育阶段的细胞命运决定中发挥着重要作用，例如在哺乳动物T细胞发育中。因此，我们通过研究海洋胎儿胸腺器官培养中的胸腺细胞发育来研究结构多样的γ -分泌酶抑制剂是否会损害Notch功能。在这里，我们发现高浓度的最有效的抑制剂在最不成熟的阶段阻断胸腺细胞的发育。相反，较低浓度或较弱的抑制剂会在后期损害分化，最明显的是抑制CD8单阳性T细胞的发育。这些表型与γ -分泌酶抑制剂对Notch信号的损害一致，并定义了胸腺细胞发育过程中连续阶段的严格Notch剂量依赖性。
In neuronal cells, presenilin-dependent gamma -secretase activity cleaves amyloid precursor proteins to release A beta peptides, and also catalyzes the release of the intracellular domain of the transmembrane receptor Notch. Accumulation of aberrant A beta peptides appears to be causally related to Alzheimer`s disease. Inhibition of A beta peptide production is therefore a potential target for therapeutic intervention. Notch proteins play an important role in cell fate determination in many different organisms and at different stages of development, for example in mammalian T cell development. We therefore addressed whether structurally diverse gamma -secretase inhibitors impair Notch function by studying thymocyte development in marine fetal thymic organ cultures. Here we show that high concentrations of the most potent inhibitors blocked thymocyte development at the most immature stage. fn contrast, lower concentrations or less potent inhibitors impaired differentiation at a later stage, most notably suppressing the development of CD8 single-positive T cells. These phenotypes are consistent with an impairment of Notch signaling by gamma -secretase inhibitors and define a strict Notch dose dependence of consecutive stages during thymocyte development.