State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
University of the Chinese Academy of Sciences, Beijing, China.
J Mol Cell Biol. 2018 Oct 1;10(5):388-401. doi: 10.1093/jmcb/mjy027.
Secretoneurin (SN) is a neuropeptide derived from specific proteolytic processing of the precursor secretogranin II (SgII). In zebrafish and other teleosts, there are two paralogs named sgIIa and sgIIb. Our results showed that neurons expressing sgIIb were aligned with central arteries in the hindbrain, demonstrating a close neurovascular association. Both sgIIb-/- and sgIIa-/-/sgIIb-/- mutant embryos were defective in hindbrain central artery development due to impairment of migration and proliferation of central artery cells. Further study revealed that sgIIb is non-cell autonomous and required for central artery development. Hindbrain arterial and venous network identities were not affected in sgIIb-/- mutant embryos, and the mRNA levels of Notch and VEGF pathway-related genes were not altered. However, the activation of MAPK and PI3K/AKT pathways was inhibited in sgIIb-/- mutant embryos. Reactivation of MAPK or PI3K/AKT in endothelial cells could partially rescue the central artery developmental defects in the sgIIb mutants. This study provides the first in vivo evidence that sgIIb plays a critical role in neurovascular modeling of the hindbrain. Targeting the SgII system may, therefore, represent a new avenue for the treatment of vascular defects in the central nervous system.
分泌脑啡肽（SN）是一种来源于前体分泌颗粒蛋白 II（SgII）特异性蛋白水解加工的神经肽。在斑马鱼和其他硬骨鱼中，有两个称为 sgIIa 和 sgIIb 的同源基因。我们的研究结果表明，表达 sgIIb 的神经元与后脑的中枢动脉排列一致，表明存在密切的神经血管关联。sgIIb-/-和 sgIIa-/-/sgIIb-/-突变体胚胎由于中枢动脉细胞迁移和增殖受损而在后脑中央动脉发育中存在缺陷。进一步的研究表明，sgIIb 是非细胞自主的，并且是中央动脉发育所必需的。sgIIb-/-突变体胚胎的后脑动脉和静脉网络特征没有受到影响，Notch 和 VEGF 通路相关基因的 mRNA 水平也没有改变。然而，sgIIb-/-突变体胚胎中 MAPK 和 PI3K/AKT 通路的激活受到抑制。内皮细胞中 MAPK 或 PI3K/AKT 的再激活可以部分挽救 sgIIb 突变体的中央动脉发育缺陷。这项研究首次提供了体内证据，表明 sgIIb 在后脑的神经血管建模中发挥关键作用。因此，靶向 SgII 系统可能为治疗中枢神经系统的血管缺陷提供新的途径。
