Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA.
Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115, USA.
Dev Cell. 2023 Sep 11;58(17):1534-1547.e6. doi: 10.1016/j.devcel.2023.06.005. Epub 2023 Jul 11.
The blood-brain barrier (BBB) is a unique set of properties of the brain vasculature which severely restrict its permeability to proteins and small molecules. Classic chick-quail chimera studies have shown that these properties are not intrinsic to the brain vasculature but rather are induced by surrounding neural tissue. Here, we identify Spock1 as a candidate neuronal signal for regulating BBB permeability in zebrafish and mice. Mosaic genetic analysis shows that neuronally expressed Spock1 is cell non-autonomously required for a functional BBB. Leakage in spock1 mutants is associated with altered extracellular matrix (ECM), increased endothelial transcytosis, and altered pericyte-endothelial interactions. Furthermore, a single dose of recombinant SPOCK1 partially restores BBB function in spock1 mutants by quenching gelatinase activity and restoring vascular expression of BBB genes including mcamb. These analyses support a model in which neuronally secreted Spock1 initiates BBB properties by altering the ECM, thereby regulating pericyte-endothelial interactions and downstream vascular gene expression.
血脑屏障（BBB）是脑血管的一组独特特性，严重限制了其对蛋白质和小分子的通透性。经典的鸡-鹌鹑嵌合体研究表明，这些特性不是脑血管所固有的，而是由周围的神经组织诱导的。在这里，我们确定 Spock1 是一种候选神经元信号，可调节斑马鱼和小鼠的 BBB 通透性。镶嵌遗传分析表明，神经元表达的 Spock1 对于功能性 BBB 是细胞非自主必需的。在 spock1 突变体中出现渗漏与细胞外基质（ECM）改变、内皮细胞转胞吞作用增加以及周细胞-内皮细胞相互作用改变有关。此外，单次给予重组 SPOCK1 通过抑制明胶酶活性和恢复 BBB 基因（包括 mcamb）的血管表达，部分恢复了 spock1 突变体的 BBB 功能。这些分析支持了这样一种模型，即神经元分泌的 Spock1 通过改变 ECM 来启动 BBB 特性，从而调节周细胞-内皮细胞相互作用和下游血管基因表达。
