由于CCM1,CCM2或CCM3基因的突变,可能会出现海绵状脑畸形。据报道,缺乏Cdc42也会在小鼠中诱导这些畸形。然而,CCM3(脑海绵状畸形3)相关激酶在海绵状瘤发展中的作用尚不清楚,而我们,因此,调查了他们在这个过程中的作用。
我们使用了体内方法的组合,使用转基因小鼠缺乏CCM3相关激酶STK24和STK25(丝氨酸/苏氨酸激酶24和25),和人内皮细胞的体外模型,其中STK24和STK25的表达被RNA干扰抑制。
同时缺乏Stk24和Stk25的小鼠,但它们中的任何一个都没有,在早期就发展出具有海绵状瘤特征的侵袭性血管病变。在Stk24杂合性的背景下,Stk25缺乏也引起了血管异常。缺乏两种激酶的人内皮细胞表现出CCM3损失的几种后果,单一STK25缺陷也诱导KLF2表达,高尔基分散体,β-连环蛋白的分布改变,和应力纤维的外观。
CCM3相关激酶STK24和STK25在抑制海绵体瘤的发展中起主要作用。
Cavernous cerebral malformations can arise because of mutations in the CCM1, CCM2, or CCM3 genes, and lack of Cdc42 has also been reported to induce these malformations in mice. However, the role of the CCM3 (cerebral cavernous malformation 3)-associated kinases in cavernoma development is not known, and we, therefore, have investigated their role in the process.
We used a combination of an in vivo approach, using mice genetically modified to be deficient in the CCM3-associated kinases STK24 and STK25 (serine/threonine kinases 24 and 25), and the in vitro model of human endothelial cells in which expression of STK24 and STK25 was inhibited by RNA interference.
Mice deficient for both Stk24 and Stk25, but not for either of them individually, developed aggressive vascular lesions with the characteristics of cavernomas at an early age. Stk25 deficiency also gave rise to vascular anomalies in the context of Stk24 heterozygosity. Human endothelial cells deficient for both kinases phenocopied several of the consequences of CCM3 loss, and single STK25 deficiency also induced KLF2 expression, Golgi dispersion, altered distribution of β-catenin, and appearance of stress fibers.
The CCM3-associated kinases STK24 and STK25 play a major role in the inhibition of cavernoma development.