From the FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy (M.C., F.O., F.B., G.V.B., A.A.M., E.D.).
Molecular Neurobiology Laboratory, Division of Neuroscience (G.P.B.), San Raffaele Hospital, Milan, Italy.
Circ Res. 2019 Feb 15;124(4):511-525. doi: 10.1161/CIRCRESAHA.118.313316.
The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.
Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/β-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/β-catenin in inducing BBB differentiation and maintenance.
Using reporter mice and nuclear staining of Sox17 and β-catenin, we report that although β-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo and progressively declines after birth. In search of Sox17 mechanism of action, RNA sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/β-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/β-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the β-catenin destruction complex or expression of a degradation-resistant β-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17.
Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB, and they underline the strict reciprocal tuning of this transcription factor and Wnt/β-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.
中枢神经系统的微血管包括血脑屏障（BBB），它调节营养物质的通透性，并限制有毒物质和炎症细胞的通过。经典的 Wnt/β-连环蛋白信号通路负责脑血管生成和 BBB 分化的早期阶段。然而，这种信号在出生后下降，而其他能够在出生后维持屏障完整性的信号通路尚不清楚。
Sox17（SRY [性别决定区 Y]-盒 17）是内皮细胞中 Wnt/β-连环蛋白的主要下游靶标，调节动脉分化。在本文中，我们询问 Sox17 是否可以作为诱导 BBB 分化和维持的 Wnt/β-连环蛋白的下游靶标。
使用报告小鼠和 Sox17 和 β-连环蛋白的核染色，我们报告尽管β-连环蛋白信号在出生后下降，但 Sox17 的激活增加，并在成年期保持高水平。内皮细胞特异性敲除 Sox17 会导致大脑微循环通透性增加。这种效应的严重程度取决于 BBB 成熟度：在胚胎中很强，出生后逐渐下降。在寻找 Sox17 作用机制的过程中，对脑内皮细胞基因表达的 RNA 测序分析鉴定了 Wnt/β-连环蛋白信号通路的成员作为 Sox17 的下游靶标。一致地，我们发现 Sox17 是 Wnt/β-连环蛋白信号的正诱导剂，它与该途径协同作用诱导和维持 BBB 特性。在体内，抑制 β-连环蛋白破坏复合物或表达一种降解抗性 β-连环蛋白突变体，可防止 Sox17 缺失时观察到的通透性增加和视网膜血管畸形。
我们的数据突出了 Sox17 在诱导和维持 BBB 中的新作用，并强调了该转录因子和 Wnt/β-连环蛋白通路的严格相互调节。调节 Sox17 活性可能与控制病理条件下 BBB 的通透性有关。
Zotero 插件
