Endothelial Unc5B controls blood-brain barrier integrity.
Endothelial Unc5B controls blood-brain barrier integrity.
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内皮Unc5B控制血脑屏障完整性。
DOI：
10.1038/s41467-022-28785-9
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发表时间：
2022-03-04
影响因子：
16.6
通讯作者：
Eichmann A
中科院分区：
文献类型：
--
作者：
Boyé K;Geraldo LH;Furtado J;Pibouin-Fragner L;Poulet M;Kim D;Nelson B;Xu Y;Jacob L;Maissa N;Agalliu D;Claesson-Welsh L;Ackerman SL;Eichmann A
血脑屏障(BBB)的完整性对中枢神经系统(CNS)的正常功能至关重要。在这里，我们表明，内皮Unc5b受体通过维持Wnt/β-catenin信号来控制血脑屏障的完整性。在成年小鼠中，可诱导的内皮特异性Unc5b的缺失导致脑毛细血管的血脑屏障泄漏，从而转变为屏障不能状态，Claudin-5减少，PLVAP表达增加。Unc5b的缺失降低了BbBWnt/β-catenin信号通路，β-catenin的过表达挽救了Unc5b突变的Bbb缺陷。在机制上，Unc5b配体Netrin-1增强了Unc5b与Wnt共同受体LRP6的相互作用，诱导其磷酸化，激活Wnt/β-catenin下游信号转导。静脉注射阻断Netrin-1与Unc5b结合的抗体会导致一过性血脑屏障破裂和Wnt信号中断，随后是神经血管屏障重新封闭。这些数据表明，Netrin-1-Unc5b信号通路是调节血脑屏障完整性的配体-受体通路，可能与中枢神经系统疾病有关。作者表明，Netrin-1-Unc5b信号通过维持Wnt/b-catenin信号来控制血脑屏障的完整性，而阻断Netrin-1与Unc5b结合的抗体的传递会导致一过性和大小选择性的BBB破坏。
Blood-brain barrier (BBB) integrity is critical for proper function of the central nervous system (CNS). Here, we show that the endothelial Unc5B receptor controls BBB integrity by maintaining Wnt/β-catenin signaling. Inducible endothelial-specific deletion of Unc5B in adult mice leads to BBB leak from brain capillaries that convert to a barrier-incompetent state with reduced Claudin-5 and increased PLVAP expression. Loss of Unc5B decreases BBB Wnt/β-catenin signaling, and β-catenin overexpression rescues Unc5B mutant BBB defects. Mechanistically, the Unc5B ligand Netrin-1 enhances Unc5B interaction with the Wnt co-receptor LRP6, induces its phosphorylation and activates Wnt/β-catenin downstream signaling. Intravenous delivery of antibodies blocking Netrin-1 binding to Unc5B causes a transient BBB breakdown and disruption of Wnt signaling, followed by neurovascular barrier resealing. These data identify Netrin-1-Unc5B signaling as a ligand-receptor pathway that regulates BBB integrity, with implications for CNS diseases. The authors show that Netrin-1-Unc5B signaling controls blood-brain barrier integrity by maintaining Wnt/b-catenin signaling and that delivery of antibodies blocking Netrin-1 binding to Unc5B causes transient and size-selective BBB breakdown.
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影响因子：
9.8
作者：
Cuervo H;Pereira B;Nadeem T;Lin M;Lee F;Kitajewski J;Lin CS
通讯作者：
Lin CS
影响因子：
11.5
作者：
Idbaih, Ahmed;Canney, Michael;Carpentier, Alexandre
通讯作者：
Carpentier, Alexandre
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre
Wnt/β-catenin信号传导控制血脑屏障的发展。
影响因子：
7.8
作者：
Liebner, Stefan;Corada, Monica;Bangsow, Thorsten;Babbage, Jane;Taddei, Andrea;Czupalla, Cathrin J.;Reis, Marco;Felici, Angelina;Wolburg, Hartwig;Fruttiger, Marcus;Taketo, Makoto M.;von Melchner, Harald;Plate, Karl Heinz;Gerhardt, Holger;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
16.2
作者：
Andreone BJ;Chow BW;Tata A;Lacoste B;Ben-Zvi A;Bullock K;Deik AA;Ginty DD;Clish CB;Gu C
通讯作者：
Gu C