ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo.
ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo.
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DOI：
10.1084/jem.20091990
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Conrad DH
中科院分区：
文献类型：
--
作者：
Gibb DR;El Shikh M;Kang DJ;Rowe WJ;El Sayed R;Cichy J;Yagita H;Tew JG;Dempsey PJ;Crawford HC;Conrad DH
解整合素和金属蛋白酶10（ADAM 10）的蛋白水解活性调节果蝇和小鼠胚胎中的细胞命运决定。然而，子宫内死亡的ADAM 10 −/−小鼠阻止了淋巴细胞中ADAM 10裂解事件的检查。为了研究它们在B细胞发育中的作用，我们产生了B细胞特异性ADAM 10敲除小鼠。有趣的是，ADAM 10的缺失阻止了整个边缘区B细胞（MZ B）谱系的发育。此外，低亲和力IgE受体CD 23的裂解严重受损，但随后的实验表明，ADAM 10通过独立的机制调节CD 23裂解和MZB发育。MZB的发展依赖于Notch 2信号传导，其需要Notch 2受体被先前未鉴定的蛋白酶蛋白水解。进一步的实验显示，Notch 2信号在ADAM 10缺失的B细胞中严重受损。因此，ADAM 10通过启动Notch 2信号传导来严格调节MZB的发展。本研究确定了ADAM 10作为体内CD 23脱落酶和B细胞发育的重要调节因子。此外，它对治疗从过敏到癌症的许多CD 23和Notch介导的病理具有重要意义。
The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10−/− mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell–specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.
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影响因子：
4.4
作者：
Kilmon, MA;Shelburne, AE;Conrad, DH
通讯作者：
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影响因子：
4.8
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影响因子：
32.4
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LECOANETHENCHOZ, S;GAUCHAT, JF;BONNEFOY, JY
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BONNEFOY, JY
影响因子：
3.3
作者：
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通讯作者：
Blobel, Carl P.
影响因子：
5.3
作者：
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通讯作者：
Weinmaster, Gerry