Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.
Notch dimerization and gene dosage are important for normal heart development, intestinal stem cell maintenance, and splenic marginal zone B-cell homeostasis during mite infestation.
复制标题
缺口二聚化和基因剂量对于螨虫侵扰期间的正常心脏发育，肠道干细胞维持和脾边缘B细胞稳态很重要。
DOI：
10.1371/journal.pbio.3000850
复制
发表时间：
2020-10
期刊：
影响因子：
9.8
通讯作者：
Kopan R
中科院分区：
文献类型：
--
作者：
Kobia FM;Preusse K;Dai Q;Weaver N;Hass MR;Chaturvedi P;Stein SJ;Pear WS;Yuan Z;Kovall RA;Kuang Y;Eafergen N;Sprinzak D;Gebelein B;Brunskill EW;Kopan R
DNA 协同结合是转录调控的一个关键特征。在这里，我们通过 CRISPR 介导的小鼠工程研究了协同性在 Notch 信号传导中的作用，其中 Notch1 和 Notch2 都不能同源或异源二聚化，这对于协同结合位于许多 Notch 调节基因附近的序列配对位点 (SPS) 至关重要。尽管大多数已知的Notch依赖性表型在Notch1/2二聚体缺陷小鼠中不受影响，但事实证明，一部分组织对协同性的丧失高度敏感。这些表型包括心脏发育、与低基因剂量相结合的生存能力受损，以及肠道，对 1% 葡聚糖硫酸钠 (DSS) 的反应而发展为溃疡性结肠炎。最引人注目的表型——性别失衡和脾边缘区 B 细胞淋巴瘤——在基因剂量减少或受到慢性毛螨侵扰的情况下出现。这项研究强调了环境在恶性肿瘤和结肠炎中的作用，并且与Notch二聚体缺陷动物中依赖于Notch的抗寄生虫免疫反应受到损害是一致的。这项研究表明，信号蛋白 Notch 的二聚化有助于体内肠道稳态。 DNA 协同结合的丧失可表现为 Notch 功能获得或丧失的表型。重要的是，螨虫感染会加剧所有表型，并引发突变动物边缘区 B 细胞过度增殖，这对尘螨过敏在人类 IBD 和癌症中的作用有影响。
Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer–deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes—gender imbalance and splenic marginal zone B-cell lymphoma—emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer–deficient animals. This study reveals that dimerization of the signaling protein Notch contributes in vivo to intestinal homeostasis. Loss of cooperative DNA binding can manifest as Notch gain- or loss-of-function phenotypes. Importantly, mite infestation exacerbates all phenotypes, and triggers marginal zone B cell hyperproliferation in mutant animals, with implications for the role of dust mite allergies in human IBD and cancer.
登录
查看更多内容
DOI：
10.1084/jem.20091990
发表时间：
2010-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
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
通讯作者：
Conrad DH
影响因子：
11.8
作者：
Gomez-Lamarca MJ;Falo-Sanjuan J;Stojnic R;Abdul Rehman S;Muresan L;Jones ML;Pillidge Z;Cerda-Moya G;Yuan Z;Baloul S;Valenti P;Bystricky K;Payre F;O'Holleran K;Kovall R;Bray SJ
通讯作者：
Bray SJ
影响因子：
10.5
作者：
BAILEY, AM;POSAKONY, JW
通讯作者：
POSAKONY, JW
影响因子：
4.8
作者：
Friedmann, David R.;Wilson, Jeffrey J.;Kovall, Rhett A.
通讯作者：
Kovall, Rhett A.
DOI：
10.1038/nrg3272
发表时间：
2012-09
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--