Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain.
Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain.
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DOI：
10.1242/dev.113746
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发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
McCarty JH
中科院分区：
文献类型：
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作者：
Hirota S;Clements TP;Tang LK;Morales JE;Lee HS;Oh SP;Rivera GM;Wagner DS;McCarty JH
发育中的中枢神经系统（CNS）中的血管生成受到神经上皮细胞的调节，尽管将这些细胞与血管耦合的基因和途径在很大程度上仍然未知。在这里，我们使用生化、细胞生物学和分子遗传学方法证明 β8 整合素 (Itgb8) 和神经毡蛋白 1 (Nrp1) 通过介导神经上皮细胞和血管内皮细胞之间的粘附和信号传导事件协同促进中枢神经系统血管生成。神经上皮中的 β8 整合素促进细胞外基质 (ECM) 结合的潜在转化生长因子 β (TGFβ) 配体的激活，并刺激内皮细胞中的 TGFβ 受体信号传导。内皮细胞中的 Nrp1 通过与 β8 整联蛋白形成细胞间蛋白复合物来抑制 TGFβ 激活和信号传导。 β8 整合素、Nrp1 或经典 TGFβ 受体的细胞类型特异性消融会导致病理性血管生成，这是由神经上皮细胞-内皮细胞粘附缺陷和经典 TGFβ 信号传导失衡引起的。总的来说，这些数据确定了一条旁分泌信号通路，该通路将神经上皮与血管连接起来，并在脑血管生成过程中精确平衡 TGFβ 信号传导。摘要：Neuropilin 1 和 β8 整合素通过介导小鼠大脑中神经上皮细胞和血管内皮细胞之间的粘附和信号传导事件来协同促进脑血管生成。
Angiogenesis in the developing central nervous system (CNS) is regulated by neuroepithelial cells, although the genes and pathways that couple these cells to blood vessels remain largely uncharacterized. Here, we have used biochemical, cell biological and molecular genetic approaches to demonstrate that β8 integrin (Itgb8) and neuropilin 1 (Nrp1) cooperatively promote CNS angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells. β8 integrin in the neuroepithelium promotes the activation of extracellular matrix (ECM)-bound latent transforming growth factor β (TGFβ) ligands and stimulates TGFβ receptor signaling in endothelial cells. Nrp1 in endothelial cells suppresses TGFβ activation and signaling by forming intercellular protein complexes with β8 integrin. Cell type-specific ablation of β8 integrin, Nrp1, or canonical TGFβ receptors results in pathological angiogenesis caused by defective neuroepithelial cell-endothelial cell adhesion and imbalances in canonical TGFβ signaling. Collectively, these data identify a paracrine signaling pathway that links the neuroepithelium to blood vessels and precisely balances TGFβ signaling during cerebral angiogenesis. Summary: Neuropilin 1 and β8 integrin cooperatively promote cerebral angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells in the mouse brain.