Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification
Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification
复制标题
DOI：
10.4049/jimmunol.168.7.3173
复制
发表时间：
2002-04-01
影响因子：
4.4
通讯作者：
McGlade, CJ
中科院分区：
文献类型：
--
作者：
French, MB;Koch, U;McGlade, CJ
保守接头蛋白Numb是一种内在的细胞命运决定因素，它通过拮抗Notch介导的信号转导发挥作用。Notch膜受体家族在多种器官系统和物种中控制细胞存活和细胞命运的决定。最近的研究已经确定了哺乳动物Notch-1信号在T淋巴细胞发育的多个阶段中的作用。我们研究了哺乳动物Numb(MNumb)在T细胞发育过程中作为Notch调节因子和细胞命运决定因素的作用。在Lck近端启动子的控制下，mNumb的转基因过表达降低了Notch-1靶基因的表达，表明mNumb在体内拮抗Notch-1信号转导。然而，尽管在胸腺细胞发育的早期阶段就表达了转基因Numb，即CD44(+)CD25(+)或CD44(-)CD25(+)，但mNumb的过度表达并未影响胸腺细胞的发育、细胞周期和存活。此外，在竞争性再繁殖实验中，mNumb转基因小鼠的骨髓在胸腺生成方面没有缺陷。我们的结果表明，mNumb在未成熟的胸腺细胞中起着Notch-1拮抗剂的作用，但在这个阶段抑制Notch-1信号并不会改变Gammadelta/Alphabeta或CD4/CD8 T细胞命运的指定。
The conserved adaptor protein Numb is an intrinsic cell fate determinant that functions by antagonizing Notch-mediated signal transduction. The Notch family of membrane receptors controls cell survival and cell fate determination in a variety of organ systems and species. Recent studies have identified a role for mammalian Notch-1 signals at multiple stages of T lymphocyte development. We have examined the role of mammalian Numb (mNumb) as a Notch regulator and cell fate determinant during T cell development. Transgenic overexpression of mNumb under the control of the Lck proximal promoter reduced expression of several Notch-1 target genes, indicating that mNumb antagonizes Notch-1 signaling in vivo. However, thymocyte development, cell cycle, and survival were unperturbed by mNumb overexpression, even though transgenic Numb was expressed at an early stage in thymocyte development (CD4(-)CD8(-)CD3(-) cells that were CD44(+)CD25(+) or CD44(-)CD25(+); double-negative 2/3). Moreover, bone marrow from mNumb transgenic mice showed no defects in thymopoiesis in competitive repopulation experiments. Our results suggest that mNumb functions as a Notch-1 antagonist in immature thymocytes, but that suppression of Notch-1 signaling at this stage does not alter gammadelta/alphabeta or CD4/CD8 T cell fate specification.